WO2006014005A1 - Pyrazole derivative - Google Patents

Abstract

A compound represented by the general formula (I): [wherein Ar1 represents the general formula (II): Ar2 represents an optionally substituted, 5- or 6-membered, aromatic heterocyclic group; and X represents the general formula (III)], a salt of the compound, or a solvate of either. Also provided is a potent platelet aggregation inhibitor which inhibits neither COX-1 nor COX-2.

Description

 Specification

 Pyrazole derivative

 Technical field

 [0001] The present invention relates to a pyrazole derivative having an inhibitory action on platelet aggregation.

 Background art

 [0002] Platelets aggregate at the time of vascular injury to form a hemostatic thrombus and play an important role in preventing bleeding. On the other hand, platelets are damaged sites in vascular endothelium, constricted parts. In some places, it aggregates and induces blood clots and emboli. These thrombi and emboli cause ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, and peripheral vascular disorder. Therefore, platelet aggregation inhibitors are used for the prevention and treatment of ischemic diseases. Among them, low-dose aspirin has long been used as a platelet aggregation inhibitor, and its effect is a meta-analysis of the results of multiple clinical trials administered to 100,000 patients. ) (See Non-Patent Document 1).

 However, aspirin has a known side effect of causing gastrointestinal bleeding, a so-called aspirin ulcer, which occurs in about 1 in 100 people regardless of the dose ( Non-Patent Document 2).

 [0003] It is known that aspirin's inhibitory action on platelet aggregation is based on the inhibitory action of cyclooxygenase. Cyclooxygenases include cycloxygenase 1 (COX-1) and cycloxygenase 2 (COX-2), but aspirin selectively and irreversibly inhibits COX-1 at low doses. Inhibition of platelet aggregation by inhibiting CO X-1 also causes aspirin ulcers (see Non-Patent Documents 3 and 4). Nonsteroidal anti-inflammatory drugs are known to selectively inhibit COX-2 and exhibit anti-inflammatory effects.

[0004] As described above, aspirin is useful as an inhibitor of platelet aggregation, but it does not have COX-1 inhibitory action because it is accompanied by gastrointestinal disorders based on its action, COX-1 inhibitory action. There is a need for platelet aggregation inhibitors. On the other hand, compound (A) (see Patent Document 1 and Non-Patent Document 5) and compound (B) (see Patent Document 2) are known as pyrazole derivatives having antithrombotic activity so far. .

 [0006] [Chemical 1]

 [0007] Patent Document 1: Japanese Patent No. 2586713

 Patent Document 2: International Publication 97Z29774 Pamphlet

 Non-Patent Document 1: BMJ, 308 卷, 81-106, 1994

 Non-Patent Document 2: BMJ, 321 卷, 1183–1187, 2000

 Non-Patent Document 3: Neurology, 57 卷, Suppl. 2, S5—S7, 2001

 Non-Patent Document 4: Drugs Today, 35 卷, 251-265, 1999

 Non-Patent Document 5: Chem. Pharm. Bull., 45 卷, 987-995, 1997

 Disclosure of the invention

 Problems to be solved by the invention

[0008] However, the IC value of collagen (誘 発) for collagen-induced platelet aggregation is 5.3 X 1

 50

0 ^_6 Μ, which shows stronger inhibitory activity against COX-2 (IC value 2.4 X 10-7)

 50

 Μ). Similarly, the platelet aggregation inhibitory action of compound (Β) is not as strong as its inhibitory activity against COX-2. As described above, inhibition of COX-2 leads to an anti-inflammatory effect, and therefore, having a COX-2 inhibitory activity is not necessarily preferred as a platelet aggregation inhibitor. An object of the present invention is to provide a potent platelet aggregation inhibitor that does not inhibit COX-1 and COX-2.

Means for solving the problem [0009] As a result of diligent research for these platelet aggregation inhibitors, the present inventors have not inhibited the pyrazole derivative forces COX-1 and COX-2 represented by the following general formula (I). The present invention was completed by finding a strong and potent platelet aggregation inhibitory action.

 That is, the present invention relates to the general formula (I)

 [0011] [Chemical 2]

[In the formula, Ar represents the general formula (II)

[0013] [Chemical 3]

[0014] (wherein Y represents CH or a nitrogen atom, R ¹ represents a lower alkyl group or a lower alkoxy group);

 Ar may be a lower alkyl group, a lower alkyl group, or an optionally substituted group.

2

 A certain rubermoyl group, a cyano group, an amino group which may be substituted, a lower alkoxy group which may be substituted and a lower alkanol group which may be substituted with 1 to 3 groups selected 5 or Represents a 6-membered aromatic heterocyclic group;

 X is the general formula (III)

[0015] [Chemical 4]

(The cyclic structure in the formula may have a nitrogen atom or an oxygen atom other than the nitrogen atom described in the above formula as a constituent atom, may be substituted lower alkyl group, may be substituted A certain rubermoyl group, an amino group that may be substituted, a hydroxyl group, a lower alkoxy group, an oxo group, a lower alkanol group, a lower alkyl sulfol group, and a halogen nuclear atom, substituted with 1 to 2 groups or atoms selected A 4- to 7-membered alicyclic heterocyclic group which may be substituted; ) Is represented. Or a solvate thereof, or a salt thereof.

 [0017] The present invention also provides a pharmaceutical composition containing the above compound, salt or solvate thereof; a pharmaceutical comprising the above compound, salt or solvate thereof as an active ingredient; , Its salts or solvates thereof as an active ingredient, and a platelet aggregation inhibitor; the above-mentioned compound, its salts or their solvates as an active ingredient for the prevention and ischemia of Z .

 The present invention also provides a method for the prevention and Z or treatment of ischemic diseases, which comprises administering the above-mentioned compound, a salt thereof or a solvate thereof as an active ingredient. The present invention further provides the use of a compound as described above, a salt thereof or a solvate thereof for pharmaceutical production.

 The invention's effect

 [0018] The compound (I), a salt thereof or a solvate thereof of the present invention has an action of strongly inhibiting platelet aggregation without inhibiting COX-1 and COX-2 and inhibiting thrombus formation. Therefore, myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris, etc.), ischemic cerebrovascular disorder (transient ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorder, artificial Occlusion after vascular replacement, Thrombotic occlusion after coronary artery interpension (coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), diabetic retinopathy 'nephropathy, heart valve replacement It is useful for prevention and Z or treatment of ischemic diseases caused by thrombus' embolism. It is also useful for prevention and Z or treatment of thromboembolism associated with vascular surgery, extracorporeal blood circulation, and the like. Furthermore, it is useful for the improvement of ischemic symptoms such as ulcer, pain, and cold feeling associated with chronic arterial occlusion.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0019] General formula (I) will be described below.

First, Ar will be described. Ar represents a group represented by the above general formula (Π). In the formula , Y is CH or a nitrogen atom, and R ¹ is a lower alkyl group or a lower alkoxy group.

 The lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert butyl group, n-pentyl group, isopentyl group, n-hexyl group, cyclopropyl group And cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopentylmethyl group and the like. Of these, a methyl group, an ethyl group or an n-propyl group is preferred, and a methyl group is particularly preferred.

 [0020] The lower alkoxy group means an alkoxy group containing the above lower alkyl group in its structure. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n butoxy group, an isobutoxy group, a tert butoxy group, an n-pentoxy group, and a cyclopentyloxy group. Of these, a methoxy group or an ethoxy group is preferable, and a methoxy group is particularly preferable.

 [0021] Therefore, Ar includes 6-methyl-3-pyridyl group, 6-ethyl 3-pyridyl group, 6-methoxy-1-pyridyl group, 6-ethoxy-1-pyridyl group, 6-methyl-3-pyridazinyl group, 6 Examples include —ethyl 3-pyridazil group, 6-methoxy 3-pyridazil group, 6-ethoxy 3-pyridazil group and the like. Of these, 6-methyl-3-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl-3-pyridazinyl group or 6-methoxy-3-pyridazinyl group is preferable.

 [0022] In particular, 6-methyl-3-pyridyl group and 6-methyl-3-pyridazinyl group are preferred for obtaining a reduction in COX-1 inhibitory action and an improvement in oral absorption.

 [0023] Next, Ar will be described. Ar is a lower alkyl group which may be substituted, lower

 twenty two

 1 to 3 groups selected from an alkyl group, an optionally substituted rubamoyl group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkoxy group and a lower alkanol group A 5- or 6-membered aromatic heterocyclic group which may be substituted with a group.

Here, as the 5-membered aromatic heterocyclic group, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, furyl group, chenyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thiazolyl group, isothiazolyl group Group, thiadiazolyl group and the like. In this Among them, a 5-membered nitrogen-containing heterocyclic group is preferable, and among them, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, or a triazolyl group is preferable. In addition, 1H-pyrrole-one-ru 1-yl group, 1H-pyrrole-2-yl group, 1H-pyrrole-3-yl group, 1H-imidazole-2-yl group, 1H-imidazole-4-yl group, 1H-pyrazole-3-yl Group, 1H pyrazole-4-yl group, thiazole-2-yl group, thiazole-4-yl group, thiazole-5-yl group, oxazole-2-yl group, oxazole-4-yl group, or 1H-1, 2, 4 A triazolyl group is particularly preferred.

[0025] Examples of the 6-membered aromatic heterocyclic group include a 6-membered nitrogen-containing aromatic heterocyclic group, and examples thereof include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrajuryl group, and a triazinyl group. it can. Among these, a pyridyl group, a pyrimidyl group and a birazinyl group are preferable. Furthermore, among these, 2-pyridyl group, 3-pyridyl group, 4-pyrimidyl group or 2-pyrazinyl group is preferable.

 [0026] The 5- or 6-membered aromatic heterocyclic group includes 1) a lower alkyl group which may be substituted, 2) a lower alkynyl group, 3) a rubamoyl group which may be substituted, and 4) a cyan group. 5) an amino group which may be substituted, 6) a lower alkoxy group which may be substituted, or 7) a lower alkanol group which may be substituted. The number of substituents is 1 or the same or different 2 to 3, preferably 1. For 6-membered aromatic heterocyclic groups, the substitution position is preferably the p-position relative to the bond to the pyrazole ring.

 [0027] 1) to 7), which are substituents of the 5- or 6-membered aromatic heterocyclic ring, will be described.

1) Lower alkyl group which may be substituted: The lower alkyl group in the lower alkyl group which may be substituted means the same as the lower alkyl group described for R ¹ above. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n butyl group, isobutyl group, tert butyl group, n pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl Group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopentylmethyl group and the like. Of these, a methyl group, an ethyl group or an n-propyl group is preferred, and a methyl group is particularly preferred.

[0028] These lower alkyl groups may be substituted with one or the same or different 2 to 3 substituents or atoms selected from a) to e) as follows. these The substituents or atoms of may be substituted with the same carbon atom in the lower alkyl group as long as they can be substituted, or may be substituted with different carbon atoms.

 [0029] a) A carbamoyl group which may be substituted with one or two lower alkyl groups which are the same or different: the force rubamoyl group is an unsubstituted force rubamoyl group or 1 to 2 It means a force rubermoyl group substituted by a lower alkyl group. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and an N-methyl-N-ethylcarbamoyl group. Among these, unsubstituted force rubermoyl group, methylcarbamoyl group or dimethylcarbamoyl group is preferred! /.

 [0030] b) Lower alkyl group, lower alkanol group and lower alkyl sulphonyl group. Amino group which may be substituted with one selected or two identical or different substituents: What is this amino group? , An unsubstituted amino group, or an amino group substituted with one or the same or different two substituents selected from a lower alkyl group, a lower alkanol group, and a lower alkylsulfonyl group.

 The lower alkyl group means the lower alkyl group.

 The lower alkanoyl group means a linear or branched alkanoyl group having 1 to 6 carbon atoms. Specific examples include a formyl group, a acetyl group, an n-propiol group, an n-butyryl group, and an isoptylyl group.

 The lower alkyl sulfo group means a sulfo group substituted with the lower alkyl group. Specifically, methylsulfol group, ethylsulfol group, n-propylsulfonyl group, isopropylsulfol group, n-butylsulfol group, isobutylsulfonyl group, tert-butylsulfol group, n-pentylsulfol group -L group, isopentylsulfol group, cyclopropylsulfol group, cyclohexylsulfol group and the like.

Therefore, the group power consisting of a lower alkyl group, a lower alkanol group and a lower alkylsulfonyl group is also selected. The amino group substituted with one or the same or different two substituents includes a methylamino group, an ethylamino group, n —Propylamino, isopropylamino, cyclopropylamino, n-butylamino, isobutylamino, cyclopentylmethylamino, dimethylamino, jetylamino, di-n-propylamino, di-n-butyl Tyramino group, N-methyl-N-ethylamino group, N-ethyl-N-n-propylamino group, N-methyl-N cyclopentylmethylamino group, formylamino group, acetylamino group, n-propio-lamino group, N-methyl-N— Acetylamino group, N-ethyl N-acetylamino group, methylsulfo-lamino group, ethylsulfo-lamino group, isopropylsulfo-lamino group, n-butylsulfo-lamino group, cyclopropylsulfo-lamino group, cyclobutanesulfo-lamino group, N-methyl-N Examples thereof include a methylsulfo-lumino group and an Nethyl-N-methylsulfo-lumino group.

[0031] c) Hydroxyl group

D) Lower alkoxy group: The lower alkoxy group means the same as the lower alkoxy group described as R ¹ , that is, an alkoxy group containing the above lower alkyl group in its structure. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, an n-pentoxy group, and a cyclopentyloxy group. Among these, a methoxy group or an ethoxy group is preferable, and a methoxy group is particularly preferable.

 [0033] e) Halogen atom: Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Of these, fluorine or chlorine is preferred, and fluorine is particularly preferred.

 [0034] 2) Lower alkynyl group: The lower alkynyl group means a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms. Specific examples include an ether group, 1-propyl group, 2-propyl group, 1-pentyl group, 2-pentyl group, 1-pentyl group, 2-pentyl group, and the like. . Of these, ethynyl group, 1-propyl group or 2-propyl group is preferred, and ethynyl group is particularly preferred.

 [0035] 3) Forced rubamoyl group that may be substituted: The forceful rubamoyl group that may be substituted is an unsubstituted force rubamoyl group or one or two of the same or different lower alkyl groups. Means a substituted rubamoyl group. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, an n-propyl-powered rubamoyl group, a dimethylcarbamoyl group, a dimethylcarbamoyl group, and an N-methylN-ethylcarbamoyl group.

 [0036] 4) Cyan group

[0037] 5) Amino group that may be substituted: An amino group that may be substituted is an unsubstituted amino group Or an amino group substituted with one or two of the same or different lower alkyl groups. Specific examples include a methylamino group, an ethylamino group, an n propylamino group, a dimethylamino group, a jetylamino group, and an N-methyl N ethylamino group. Of these, an unsubstituted amino group, methylamino group or dimethylamino group is preferred.

[0038] 6) Lower alkoxy group that may be substituted: The lower alkoxy group in the lower alkoxy group that may be substituted is the same as the lower alkoxy group described above as R ¹ , An alkoxy group containing an alkyl group in its structure is meant. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tertbutoxy group, an n-pentoxy group, and a cyclopentyloxy group. Of these, a methoxy group or an ethoxy group is preferred, and a methoxy group is particularly preferred. In this case, the lower alkyl group may be further substituted with 1 to 3 groups or atoms selected from a) to e) force as in the lower alkyl group mentioned in 1) above. . The lower alkoxy group that may be substituted is preferably a methoxy group, an ethoxy group, or a strong rubamoylmethoxy group, which is preferably an unsubstituted lower alkoxy group or a lower alkoxy group substituted with a strong rubamoyl group. Most preferred is a methoxy group or a rubamoylmethoxy group.

 [0039] 7) Lower alkanoyl group: The lower alkanoyl group is the same as the lower alkanol group described in the above b), and means an alkanoyl group containing the lower alkyl group in its structure. Of these, an acetyl group or n-propionyl group is preferred, and an acetyl group is particularly preferred.

 [0040] Among these substituents, an optionally substituted lower alkyl group, unsubstituted carbamoyl group, cyano group, unsubstituted amino group, unsubstituted lower alkoxy group or lower alkanol group Is preferred.

 [0041] Accordingly, a specific example of Ar that may be substituted is a 5- or 6-membered aromatic heterocyclic group

2 Examples include pyrrolyl group, methyl pyrrolyl group, ethyl pyrrolyl group, strong rubamoyl pyrrolyl group, dimethylcarbamoyl pyrrolyl group, cyano pyrrolyl group, methoxy pyrrolyl group, amino pyrrolyl group, methylamino pyrrolyl group, dimethylamino pyrrolyl group. Group, hydroxymethylpyrrolyl group, aminomethylpyrrolyl group, methylaminomethylpyrrolyl group, dimethylaminomethylpyrrolyl group , Acetyl pyrrolyl group, pyrazolyl group, methyl pyrazolyl group, force rubamoyl virazolyl group, dimethylcarbamoyl virazolyl group, cyanopyrazolyl group, methoxypyrazolyl group, amino virazolyl group, methylamino virazolyl group, dimethylamino pyrazolyl group Group, hydroxymethylpyrazolyl group, aminomethylvirazolyl group, methylaminomethylvirazolyl group, dimethylaminomethylpyrazolyl group, acetylyl azolyl group, imidazolyl group, methylimidazolyl group, carbamoylimidazolyl group, Dimethylcarbamoylimidazolyl group, Cyanimidazolyl group, Methoxyimidazolyl group, Aminoimidazolyl group, Methylaminoimidazolyl group, Dimethylaminoimidazolyl group, Hydroxymethylimidazolyl group, Aminomethylimidazolyl group , Methylaminomethyl imidazolyl group, dimethylaminomethyl imidazolyl group, acetyl imidazolyl group, thiazolyl group, methyl thiazolyl group, aminothiazolyl group, triazolyl group, methyl triazolyl group, rubamoyl triazolyl group, dimethylcarbamoyl triazolyl group, cyanotri Azolyl group, methoxytriazolyl group, aminotriazolyl group, methylaminotriazolyl group, dimethylaminotriazolyl group, hydroxymethyltriazolyl group, aminomethyltriazolyl group, methylaminomethyltriazolyl Group, dimethylaminomethyltriazolyl group, acetiltriazolyl group, pyridyl group, methylpyridyl group, fluoromethylpyridyl group, rubamoylpyridyl group, dimethylcarbamoylpyridyl group, cyanopyridyl group Methoxypyridyl group, Aminopyridyl group, Methylaminopyridyl group, Dimethylaminopyridyl group, Hydroxymethylpyridyl group, Aminomethylpyridyl group, Methylaminomethylpyridyl group, Dimethylaminomethylpyridyl group, Acetylpyridyl group, Pyridazil group, methylbilidazil group, force rubamoylbilidazil group, dimethylcarbamoylbilidazil group, cyanobylidyl group, methoxypyridazinyl group, aminobilidazinyl group, methylaminobilidazinyl group, Dimethylaminopyridazil group, hydroxymethylpyridazil group, aminomethylbiridazil group, methylaminomethylbiidazinyl group, dimethylaminomethylbiidazinyl group, acetylylpyrimidyl group , Pyrimidyl group, methylpyrimidyl group, force rubamoyl pyrimidyl group, dimethyl group Tylcarbamoylpyrimidinyl, cyanopyrimidyl, methoxypyrimidinyl, aminovirimidinyl, methylaminopyrimidinyl, dimethylaminopyrimidyl, hydroxymethylpyrimidyl, aminomethylpyrimidyl Group, methylaminomethylpyrimidyl group, dimethylaminomethylpyrimidinyl group, acetylylpyrimidyl group, pyrajuryl group, methylbirazinyl group, Power ruberamoyl viradyl group, dimethyl carbamoyl viradyl group, cyanobirajul group, methoxypyrazinyl group, aminoviradyl group, methylaminopyrazinyl group, dimethylaminopyrazuryl group, hydroxymethylpyrazuryl group, aminomethylpyrazinyl group , Methylaminomethyl viradyl group, dimethylaminomethyl virazinyl group, acetyl biladil group, oxazolyl group, methyl oxazolyl group, rubamoyl oxazolyl group, dimethyl carbamoyl oxazolyl group, sia Noxazolyl, methoxyoxazolyl, aminooxazolyl, methylaminooxazolyl, dimethylaminooxazolyl, hydroxymethyloxazolyl, aminomethyloxazolyl, methylaminomethyl Oxazolyl group, dimethylaminomethyl Okisazoriru group, and a § cetyl O hexa benzotriazolyl group.

 Among these, pyrrolyl group, methyl pyrrolyl group, hydroxymethyl pyrrolyl group, ethyl pyrrolyl group, strong rubamoyl pyrrolyl group, acetyl pyrrolyl group, imidazolyl group, methyl imidazolyl group, pyrazolyl group, methyl pyrazolyl group, Thiazolyl group, methylthiazolyl group, aminothiazolyl group, methyltriazolyl group, methoxyoxazolyl group, methyloxazolyl group, pyridyl group, methylpyridyl group, rubamoylpyridyl group, cyanopyridyl group, aminopyridyl group, methoxy Pyridyl group, hydroxymethylpyridyl group, aminomethylpyridyl group, fluoromethylpyridyl group, pyrimidyl group, methylpyrimidinyl group, pyrajuryl group, methylbilazyl group, rubamoylviradyl group or aminoviradyl group are preferred. ,.

[0043] More specifically, 1H pyrrole 1-yl group, 3-methyl 1H pyrrole 1-yl group, 3 hydroxymethyl-1H pyrrole-1-yl group, 3 aminomethyl-1H pyrrole 1- Group, 3-methylaminomethyl- 1H pyrrole- 1-yl group, 3-dimethylaminomethyl- 1H-pyrrole 1-l group, 3-force rubamoyl 1H pyrrole 1-yl group, 1H-pyrrole 2-ru Group, 1-methyl- 1H—pyrrole 2-yl group ゝ 1H pyrrole—3-yl group, 1-methyl—1H pyrrole—3-yl group, 1-ethyl — 1H pyrrole—3-yl 1-aminoethyl-1H pyrrole-3-yl group, 1-acetyl 1H-pyrrole 3-yl group, 1H-imidazole 2-yl group, 1 methyl 1H-imidazole 2-yl group, 1H-imidazole 4-yl group, 1-methyl- 1 H-imidazole 4 I group, 1H Pirazoru 3 I group, 1H Pirazoru 4 Iru group, 1-methyl-1H Pirazoru 3 I group, 1-methyl-1H-pyrazole 4-yl group, thiazole-2-yl group, thiazole-4-yl group, thiazole-5-yl group, 2-methyloxazole-4-yl group, 5-methoxyoxazole-2-yl group, 1H-1 , 2, 4 Triazole— 3-yl group, 1-methyl 1H— 1, 2, 4 Triazol luo 3-yl group, 2 Pyridyl group, 3 Pyridyl group, 4 Pyridyl group, 3-Methoxy-2- Pyridyl Group, 3-methyl-2 pyridyl group, 4-methyl-2 pyridyl group, 4 ethyl —2 pyridyl group, 4 cyano 2 pyridyl group, 4-strength rubamoyl-2 pyridyl group, 4 —methoxy-1-pyridyl group, 4 ethoxy 2-pyridyl group, 4 amino one 2-pyridyl group, _{4-methylamino-2-pyridyl} group, 4 Jimechiruamino one 2-pyridyl group, 4 amino-methyl-2-pyridyl group, 4-methyl § amino methyl pyridyl group, 4-dimethyl § amino methyl-2 pyridinium Group, 5-methyl-2-pyridyl group, 5-ethyl-2-pyridyl group, 5-methoxy-2-pyridyl group, 5-force rubamoylmethoxy-2-pyridyl group, 5-cyano-2-pyridyl group, 5-amino-2-pyridyl group 5-methylamino-2-pyridyl group, 5-dimethylamino 2 pyridyl group, 5-force rubamoyl-2-pyridyl group, 5-methylcarbamoyl-2 pyridyl group, 5 dimethylcarbamoyl-2-pyridyl group, 5 hydroxymethyl-2-pyridyl group, 5 Aminomethyl-2 pyridyl group, 5-methylaminomethyl-2-pyridyl group, 5 dimethylaminomethyl-2 pyridyl group, 5 fluoromethyl-2 pyridyl group, 6-methoxy-2 pyridyl group, 6-methyl-2-pyridyl group, 6-methyl-3 — Pyridyl group, 6-methoxy-1-3-pyridyl group, 6-amino-1-3-pyridyl group, 3-pyridazi- 6-methoxy-3-pyridazil group, 6-methyl-3-pyridazil group, 2 pyrimidyl group, 5-methoxy-2-pyrimidyl group, 5-methyl-2-pyrimidyl group, 4-pyrimidyl group Preferred is a disulfide group, 2-pyrazuryl group, 5-methoxy-2-pyrazuryl group, 5-methyl-2-virazinyl group or 5-amino-2-birazinyl group.

Among these, 1H pyrrole-1-yl group, 3-methyl 1H pyrrole-1-yl group, 3 hydroxymethyl-1H pyrrole-1-yl group, 3 aminomethyl-1H-pyrrole 1-yl group , 3 methylaminomethyl- 1H-pyrrole 1-yl group, 3-force rubamoyl 1H-pyrrole 1-yl group, 3 dimethylaminomethyl-1H pyrrole 1-yl group, 1H-pyrrole 2-il group, 1-methyl- 1H-pyrrole 2-yl group 2 1H pyrrole-3-yl group, 1-methyl-1H pyrrole-3-yl group, 1-ethyl — 1H pyrrole— 3-yl group, 1-aminoethyl— 1H pyrrole— 3-yl group, 1- acetylyl 1H—pyrrole 3-yl group, 1H—imidazole-2-yl group, 1 methyl 1H -Imidazole-2-yl group, 1H-imidazole-4-yl group, 1-methyl-1 H-imidazole-4-yl group, 1H pyrazole-3-yl group, 1-methyl-1H pyrazole-3-yl group, 1H pyrazole-4-yl group, 1-methyl-1H pyrazole 4-yl group, thiazole-2-yl group, thiazole-4-yl group, thiazol-5-yl group, 1-methyl-1,2,4 卜 triazole-3-yl group, 2 pyridyl group, 3 Pyridyl group, 4-pyridyl group, 3-methoxy1-2pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 4-amino-2 pyridyl group, 5-methyl-2-pyridyl group, 5-ethyl-2 Zyl group, 5-methoxy-2-pyridyl group, 5-force rubamoyl methoxy-2 pyridyl group, 5 cyano-2-pyridyl group, 5-force rubamoyl-2 pyridyl group, 5- cyano-2-pyridyl group, 5-amino-2-pyridyl group, 5-hydroxymethyl-2-pyridyl group, 5-aminomethyl-2-pyridyl group, 5-fluoromethyl-2-pyridyl group, 6-methyl-2-pyridyl group, 6-methoxy-2-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl 3-Pyridyl group, 6-Amino-1-3-Pyridyl group, 6-Methoxy-1-3-Pyridazil group, 6-Methyl-3 Pyridazil group, 2-Pyrimidyl group, 5-Methoxy-2-Pyrimidyl group 5-methyl-2-pyrimidyl group, 4-pyrimidyl group, 2-pyrazuryl group, 5-methoxy-2-pyrazuryl group, 5-methyl-2-pyrazuryl group, or 5-amino-2-pyrazinyl group. Good.

Among them, 1H pyrrole 1-yl group, 3 hydroxymethyl 1 1H pyrrole 1ru 1yl group, 1H pyrrole-2-yl group, 1H pyrrole-3-yl group, 1-methyl- 1H pyrrole-3-yl group, 1-ethyl-1H pyrrole-3-yl group, 1-aminoethyl-1H pyrrole-3-yl group, 1-acetylyl 1H pyrrole-3-yl group, 1H imidazole 2-yl group, 1-methyl-1H imidazole-4-yl group, 1H pyrazole-3-yl group, 1-methyl-1H pyrazole-3-yl group, 1-methyl-1,2,4 triazole-3-yl group , Thiazole-2-yl group, thiazole-5-yl group, 2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 5 aminomethyl-2-pyridyl group, 5 hydroxymethyl-2-pyridyl group, 5 fluoro Romethyl-2-pyridyl group, 5-cyanol-2-pyridyl group, 5-force rubamoyl-2-pyridyl group, 5-methoxy-2-pyridyl group, 4-pyrimidinyl group, 2-pyrazuryl group, 5-methyl-2-pyrudyl group or 5-amino-2-pyrazuryl group Most preferred!

 Next, X will be described. X represents a group represented by the general formula (III).

I) means a 4- to 7-membered alicyclic heterocyclic group which may contain a nitrogen atom or an oxygen atom in addition to the nitrogen atom described in the general formula (ii).

 [0047] Examples of the 4- to 7-membered alicyclic heterocyclic group include azetidyl group, pyrrolidyl group, vilazolidyl group, piperidyl group, piperazinyl group, hexahydropyridazil group, hexahydropyridyl group, A midyl group, an imidazolidyl group, a homopiperazyl group, a morpholinyl group, an oxazepar group, and the like can be given. Of these, azetidinyl group, pyrrolidyl group, bisazolyl group, piperidinyl group, piperazyl group, hexahydropyridazinyl group, morpholinyl group and oxazepar group are particularly preferable.

 [0048] These alicyclic heterocyclic groups are further substituted with one or the same or different 2 to 4 groups or atoms selected from the following substituents (i) to (ix). May be.

 (I) Lower alkyl group that may be substituted: The lower alkyl group that may be substituted is the same group as the lower alkyl group that may be substituted described as the substituent of Ar.

2

means. That is, the above a) to e) force represents a selected group or a lower alkyl group which may be substituted by 1 to 3 atoms. Furthermore, the lower alkyl group may be substituted with an oxo group alone, or a) to e) force may be substituted in combination with a group or atom selected. Examples of the lower alkyl group include the lower alkyl groups, and among these, a methyl group or a cyclopropyl group is particularly preferable. Furthermore, the group or atom substituted on the lower alkyl group is preferably a halogen atom, a hydroxyl group, a lower alkoxy group or an amino group. Therefore, the lower alkyl group substituted on the cyclic structure in formula (ΠΙ) is preferably a halogeno lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group or an amino lower alkyl group. The halogeno lower alkyl group means the lower alkyl group substituted with the halogen atom. Specific examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group. Among these, a methyl group, a fluoromethyl group, A difluoromethyl group or a trifluoromethyl group is preferred, and a fluoromethyl group is particularly preferred. The hydroxy lower alkyl group means the lower alkyl group substituted with a hydroxyl group, specifically, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, 2 Examples thereof include a hydroxypropyl group and a 3 hydroxypropyl group. The lower alkoxy lower alkyl group means a lower alkyl group substituted with the lower alkoxy group, and examples thereof include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, and an ethoxyethyl group. Of these, a methoxymethyl group is preferred. The amino lower alkyl group means the lower alkyl group substituted with an amino group, and specifically includes an aminomethyl group, a 2-aminoethyl group, a 1-aminocyclopropyl group, and the like. Aminocyclopropyl group is preferred.

(Ii) Forced rubamoyl group that may be substituted: Examples of the forceful rubamoyl group that may be substituted include those similar to the above-mentioned Ar substituent 3). Among these, no substitution

 2

 Of these, a rubamoyl group, a methylcarbamoyl group or a dimethylcarbamoyl group is preferred, and an unsubstituted rubamoyl group is particularly preferred.

 (Iii) Amino group that may be substituted: As the amino group that may be substituted,

 2 The same as the amino group mentioned as the substituent 5) can also be mentioned. Among these, an unsubstituted amino group, a methylamino group, a dimethylamino group, an ethylamino group, or a jetylamino group is preferable, and an unsubstituted amino group or a dimethylamino group is particularly preferable.

[0052] (iv) Hydroxyl group

[0053] (V) a lower alkoxy group: the lower the alkoxy group include those similar to the R ^1, main butoxy group or an ethoxy group is preferred is preferable instrument especially methoxy groups.

[0054] (vi) year-old kiso group

 [0055] (vii) Lower alkanoyl group: The lower alkanol group means a linear or branched alkanoyl group having 1 to 6 carbon atoms as described above. Specific examples include a formyl group, a acetyl group, an n-propiol group, an n-ptylyl group, an isoptylyl group, a bivaloyl group, etc. Among them, a formyl group is particularly preferable.

[0056] (viii) Lower alkyl sulfol group: Examples of the lower alkyl sulfol group include the same as described above. That is, a sulfonyl group substituted with the lower alkyl group Specifically, methylsulfol group, ethylsulfol group, n-propylsulfol group, isopropylsulfol group, n-butylsulfol group, isobutylsulfol group, tert-butylsulfol -L group, n-pentylsulfol group, isopentylsulfol group, cyclopropylsulfol group, cyclohexylsulfol group and the like. Of these, a methylsulfol group, an ethylsulfol group or an n-propylsulfonyl group is preferred.

 (Ix) Halogen atom: The same as mentioned above. Of these, fluorine or chlorine is preferred, and fluorine is particularly preferred.

[0058] In these (i) to (ix) forces, one or more selected groups or atoms may be substituted, and as long as they can be substituted, 2 to 4 identical or different substituents may be substituted. Also good. When a plurality of groups are substituted, they may be substituted with the same element of the alicyclic heterocyclic group or may be substituted with different elements.

 [0059] As the general formula (式), specifically, azetidine 1-yl group, 3 oxazetidine

 1-yl group, 2 oxazetidine 1-yl group, 3 aminoazetidine 1-yl group, 3 methylaminoazetidine 1-yl group, 3 dimethylaminoazetidine 1-yl group, 2 methylazetidine 1-yl group, 3 methylazetidine 1-yl group, 2 , 2-dimethylazetidine 1-yl group, 3, 3 dimethylazetidine 1-yl group, 2, 2-dimethyl3 dimethylaminoazetidine 1-yl group, 2 hydroxymethylazetidine 1-yl group, 3 hydroxy Methylazetidine 1-yl group, 2 Fluoromethyl azetidine 1-yl group, 3 Fluoromethyl azetidine 1-yl group, 3-Methoxyazetidine 1-yl group, 2-Strength rubamoylazetidine 1-yl group, 2-Methylcarbamo Lilazetidine 1-yl group, 2 dimethylcarbamoylazetidine 1-yl group, 3 —Methylcarbamoylazetidine 1-yl group, 3 dimethylcarbamoylazetidine 1-yl group, 3, 3 difluoroazetidine 1-yl group;

[0060] pyrrolidino group, 2-methylpyrrolidino group, 2-ethylpyrrolidino group, 2-aminomethylpyrrolidino group, 2-methylaminomethylpyrrolidino group, 2-dimethylaminomethylpyrrolidino group, 2-hydroxyl Methylpyrrolidino group, 2-methoxymethylpyrrolidino group, 2-fluoromethylpyrrole Dino group, 2 trifluoromethylpyrrolidino group, 2,2 dimethylpyrrolidino group, 2,3 dimethylpyrrolidino group, 2,4 dimethylpyrrolidino group, 2,5 dimethylpyrrolidino group, 2 carbamoylpyrrolidino group 2-methylcarbamoylpyrrolidino group, 2-dimethylcarbamoylpyrrolidino group, 2-methoxypyrrolidino group, 2-oxopyrrolidino group, 2,5 dioxopyrrolidino group, 2-methoxymethyl-5-methylpyrrolidino group, 2,2 dimethyl- 3 Dimethylaminopyrrolidino group, 3-methylpyrrolidino group, 3-methoxymethylpyrrolidino group, 3-fluoromethylpyrrolidino group, 3-trifluoromethylpyrrolidino group, 3-aminominopyrrolidino group, 3-methylaminominopyrroline Dino group, 3-dimethylaminopyrrolidino group, 3-oxopyrrolidino group, 3,3-dimethylpyrrolidino group, 3-hydroxymethylpyrrolidino group, 3-force rubamoylpyrrolidino group, 3-methylcarbamoylpyrrolidino group, 3-dimethylcarbamoylpyrrolidino group, 3-methoxypyrrolidino group, 3-fluoropyrrolidino group, 3 , 3-Difluoropyrrolidino group;

 [0061] Imidazolidine 1-yl group, 3-methylimidazolidine 1-yl group, 2-oxoimidazolidine 1-yl group, 4-oxoimidazolidine 1-yl group, 3-methyl 2-oxomidylidine 1 —Yl group, 3-methyl 4-oxoimidazolidine 1-yl group, 2,2-dimethylimidazoline 1-yl group;

 [0062] Virazolidine 1-yl group, 2-Methylvirazolidine 1-yl group, 3-Oxovirazolidin 1-yl group, 3, 5 Dioxopyrazolidine 1-yl group, 2 Formyl-virazolidin— 1-yl group, 2-methylsulfol-pyrazolidine 1-yl group;

[0063] piperidino group, 2-oxopiperidino group, 3-oxopiperidino group, 4-oxopiperidino group, 2 hydroxypiperidino group, 3 hydroxypiperidino group, 4-hydroxypiperidino group, 2-methoxypi Peridino group, 3-methoxypiperidino group, 4-methoxypiperidino group, 3 aminobiperidino group, 4 aminobiperidino group, 3-methylaminobiperidino group, 4-methylaminopiperidino group, 3 dimethylaminobiperidino group 4-dimethylaminobiperidino group, 2-methylpiperidino group, 3-methylbiperidino group, 4-methylbiperidino group, 2,2 dimethylbiperidino group, 3,3-dimethylbiperidino group, 4,4 dimethyl Biperidino group, 3-fluoropiperidino group, 4 fluoropiperidino group, 4 chloropiperidino group, 3, 3-difluoropiperidino group, 4, 4 Difluoromethyl O Ropi piperidino group, 3, 3-dichloro-piperidinocarbonyl group, 4, 4 Jiku Roropiperijino group, 4 full O b piperidino group, 2-hydroxy-piperidino group, 3 hydroxymethylpiperidino group, 4-hydroxymethylpiperidino group, 2-strength rubamoyl piperidino group, 3-strength rubamoylbiperidino group, 4strength rubamoylbiperidino group, 2-methylcarbamoylbiperidi Group, 3-methylcarbamoylbiperidino group, 4-methylcarbamoylbiperidino group, 2 dimethylcarbamoylbiperidino group, 3 dimethylcarbamoylbiperidino group, 4 dimethylcarbamoylbiperidino group, 2-methoxymethylbiperidino group, 3 —Methoxymethylbiperidino group, 4-methoxymethylbiperidino group, 2 aminomethylpiperidino group, 3 aminomethylbiperidino group, 4 aminomethylbiperidino group, 2-methylaminomethylbiperidino group, 3 —Methylaminomethyl biperidino group, 4-methylaminomethyl piperidino group, 2 dimethyl Minomethylbiperidino group, 3 dimethylaminomethylbiberidino group, 4 dimethylaminomethylbiperidino group, 2 aminoethylpiperidino group, 3 aminoethylbiperidino group, 4 aminoethylpiperidino group, 2 methylamino Ethylpiperidino group, 3 methylaminoethylpiperidino group, 4 methylaminoethylpiperidino group, 2 dimethylaminoethylpiperidino group, 3-dimethylaminoethylpiperidino group, 4-dimethylaminoethylylbi A peridino group, a 2-aminocyclopropylpiperidino group;

Piperazino, 2-oxopiperazino, 3-oxopiperazino, 2-oxo-4-methylbiperazino, 3-oxo-4-methylbiperazino, 3-oxo-4-ethylbiperazino, 4-formylpiperazino, 2, 3 di Oxopiperazino group, 3,5 dioxopiperazino group, 2,6 dioxopiperazino group, 2,3 dixo 4-methylbiperazino group, 3,5 dioxo4-methylbiperazino group, 2, 6 Dioxo 4-methylbiperazino group, 2-methylbiperazino group, 3-methylbiperazino group, 4-methylbiperazino group, 2 ethyl piperazino group, 3 ethylbiperazino group, 4-ethylbiperazino group, 2 isopropylpiperazino group Group, 3 isopropyl piperazino group, 4 isopropyl piperazino group, 2 cyclopropyl piperazino group, 3-cyclopropyl piperazino group, 4-cyclop Lopylpiperazino group, 4-cyclobutylpiperazino group, 2,2 dimethylbiperazino group, 3,3 dimethylbiperazino group, 2,3 dimethylbiperazino group, 2,4 dimethylbiperazino group, 3,4 dimethyl Tilpiperazino group, 3,5 dimethylbiperazino group, 2,6 dimethylbiperazino group, 2-ethyl 4-methylbiperazino group, 3-ethyl 4-methylbiperazino group, 2 isopropyl 4-methylbipera Dino group, 3 isopropyl-4-methylbiperazino group, 2 cyclo Propyl-4-methylbiperazino group, 3 Cyclopropyl-4-methylbiperazino group, 1, 2, 6 Trimethylbiperazino group, 3, 4, 5 Trimethylbiperazino group, 2, 2, 4 Trimethylpiperazino group 3, 3, 4-trimethylbiperazino group, 3, 3, 4-trimethyl 5-oxopiperazino group, 2, 2, 4 trimethyl 3-oxopiperazino group, 4 acetylbiperazino group, 2 hydroxymethyl Piperazino group, 3-hydroxymethylpiperazino group, 4-methoxypiperazino group, 2-methoxymethylbiperazino group, 3-methoxymethylbiperazino group, 2 hydroxychichetyl piperazino group, 3-hydroxy Ethylpiperazino group, 4-hydroxyethylpiperazino group, 2 hydroxymethyl-4-methylbiperazino group, 3 hydroxymethyl-4 —methylbiperazino group, 2-methoxymethyl-4-methyl Rubiperazino group, 3-methoxymethyl 4-methylbiperazino group, 2 hydroxyethyl 4-methylbiperazino group, 3 hydroxyxetyl 4 methylbiperazino group, 2 methoxyethyl 4 methylbiperazino group, 3-methoxyethyl-4-methylbiperazino group , 2-force rubamoyl biperazino group, 3-force rubamoyl biperazino group, 4 one-strength rubamoyl biperazino group, 2-methylcarbamoyl biperazino group, 3-methylcarbamoyl biperazino group, 4- Methyl carbamoyl biperazino group, 2 dimethyl carbamoyl biperazino group, 3 dimethyl carbamoyl biperazino group, 4 dimethyl carbamoyl biperazino group, 2-force rubamoyl methyl biperazino group, 3—force rubamoyl methyl piperazi Group, 4 rubamoylmethylpiperazino group, 2 methylcarbamoylmethylbipe Dino group, 3-methylcarbamoylmethylbiperazino group, 4 methyl-powered rubamoylbiperazino group, 2 dimethylcarbamoylmethylbiperazino group, 3 dimethylcarbamoylmethylbiperazino group, 2-powered rubamoyl 4-methylbipera Dino group, 3--strong rubamoyl- 4-methylbiperazino group, 4-strength rubamoylbiperazino group, 2-methylcarbamoyl 4-methylpiperazino group, 3-methylcarbamoyl 4-methylpiperazino group, 4-methylcarbamoylbiperazino group , 2 Dimethylcarbamoyl 4-methylbiperazino group, 3-Dimethylcarbamoyl 4-methylbiperazino group, 4 Dimethylcarbamoylbiperazino group, 2-Force ruberamoylmethyl-4-methylbiperazino group, 3-Strength rubermoylmethyl-4 -Methylbiperazino group, 4 rubamoylmethylbiperazino group 2-methylcarbamoyl-methyl 4-methylpiperazino group, 3-methylcarbamoyl-methyl 4-methyl-bi Pella Gino group, 4-methylcarbamoyl-bi Pella Gino group, 2-dimethyl carbamoylthiopheno 4-methylpiperazino group, 3-dimethylcarbamoylmethyl 4-methylpiperazino group, 2 aminomethylbiperazino group, 3 aminomethylbiperazino group, 2-methylaminomethylbiperazino group, 3 methylaminomethylbiperazino group, 2 dimethylaminomethyl piperazino group, 3 dimethylaminomethylbiperazino group, 2 aminoethylpiperazino group, 3 aminoethylpiperazino group, 4 aminoethylpiperazino group, 2 methylaminoethylpiperazino group, 3 —Methylaminoethylpiperazino group, 4 Methylaminoethylpiperazino group, 2 Dimethylaminoethylpiperazino group, 3 Dimethylaminoethylpiperazino group, 4 Dimethylaminoethylpiperazino group, 2 Aminomethyl-4-methyl Biperazino group, 3-aminomethyl 4-methylbiperazino group, 2-methylamino Methyl 4 Methylbiperazino group, 3 Methylaminomethyl-4-Methylbiperazino group, 2 Dimethylaminomethyl-4-methylpiperazino group, 3 Dimethylaminomethyl-4-methylbiperazino group, 2 Aminoethyl 4-Methylbipera Dino group, 3 aminoethyl-4-methylbiperazino group, 2 methylaminoethyl 4 methylbiperazino group, 3-methylaminoethyl 4 methylbiperazino group, 2 dimethylaminoethyl-4-methylbiperazino group, 3 dimethylaminoethyl-4 -Methylbiperazino group, 4-methylsulfo-biperazino group;

Morpholino group, 2 methylmorpholino group, 3 methylmorpholino group, 2 ethylmorpholino group, 3 ethinoremonoreforino group, 2, 2 dimethinoremonoreforino group, 3, 3 dimethinoremonoreforino group, 3 methyl Morpholine 4-yl group, 2 hydroxymethylmorpholino group, 3 hydroxymethylmorpholino group, 2-methoxymethylmorpholino group, 3-methoxymethylmorpholino group, 2 hydroxyethylmorpholino group, 3 hydroxyethyl morpholino group, 2-methoxyethyl Morpholino group, 3-methoxyethyl morpholino group, 2-strength rubamoyl morpholino group, 3 monostrept rubamoyl morpholino group, 2-methylcarbamoyl morpholino group, 3-methylcarbamoyl morpholino group, 2 dimethylcarbamoyl morpholino group, 3 dimethylcarba Moi morpholino group, 2-strength rubamo Ylmethylmorpholino group, 3-force rubamoylmethylmorpholino group, 2-methylcarbamoylmethylmorpholino group, 3-methylcarbamoylmethylmorpholino group, 2 dimethylcarbamoylmethylmorpholino group, 3 dimethylcarbamoyl methylmorpholino group, 2-force Rubamoylethyl morpholino group, 3-force rubamoylethyl morpholino group, 2-methylcarbamoylethyl morpholino group, 3-methylcarbamoyl group Tylmorpholino group, 2 Dimethylcarbamoylethylmorpholino group, 3 Dimethylcarbamoylethylmorpholino group, 2-Aminomethylmorpholino group, 3-Aminomethylmorpholino group, 2-Methylaminomethylmorpholino group, 3-Methyl Aminomethylmorpholino group, 2 Dimethylaminomethylmorpholino group, 3 Dimethylaminomethylmorpholino group, 2 Aminoethylmorpholino group, 3 Aminoethylmorpholino group, 2 Methylaminoethylmorpholino group, 3 Methylaminoethylmorpholino group, 2 Dimethyl Aminoethylmorpholino group, 3 dimethylaminoethylmorpholino group;

Hexahydropyridazine 1-yl group, 2-Formylhexahydropyridazine 1-yl group, 2 Acetylhexahydropyridazine 1-yl group, 3 Exohexahydropyridazine 1-yl group, 6 Exohexahydropyridazine 1-yl group, 4-aminohexahydropyridazine 1-yl group, 4-methylaminohexahydropyridazine 1-yl group, 4-dimethylaminohexahydropyridazine 1-yl group, 2-methylhexahydropyridazine 1-yl group, 3-methylhexahydropyridazine 1-yl group Group, 4-methylhexahydropyridazine 1-yl group, 2, 3 dimethylhexahydropyridazine 1-yl group, 3, 3 dimethylhexahydropyridazine 1-yl group, 4,4-dimethylhexahydropyridazine 1-yl group, 3 hydroxy Methylhexahydropyridazine 1-yl group, 4- Hydroxymethylhexahydropyridazine 1-yl group, 5 Hydroxymethylhexahydropyridazine 1-yl group, 6 Hydroxymethylhexahydropyridazine 1-yl group, 2-Force ruvamoylhexahydropyridazine 1-yl group, 3-force ruvamoyl Oxahydropyridazine 1-yl group, 4 one-strength ruberamoylhexahydropyridazine 1-yl group, 5-strength rubamoyl hexahydropyridazine 1-yl group, 6-strength rubamoylhexahydropyridazine 1-yl group, 2-methylcarbamoylhexahydro Pyridazine 1-yl group, 3-methylcarbamoylhexahydropyridazine 1-yl group, 4-methylcarbamoylhexahydropyridazine 1-yl group, 5-methylcarbamoylhexahydropyridazine 1-yl group, 6-methylcarbamoyl Hexahydropyridazine 1 Group, 2-dimethylcarbamoylhexahydropyridazine 1-yl group, 3 dimethylcarbamoylhexahydropyridazine 1-yl group, 4 dimethylcarbamoylhexahydropyridazine 1-yl group, 5 dimethylcarbamoylhexahydropyridazine 1-yl group, 6 To dimethylcarbamoyl Oxahydropyridazine 1-yl group, 3-methoxymethylhexahydropyridazine 1-yl group, 4-methoxymethylhexahydropyridazine 1-yl group, 5-methoxymethylhexahydropyridazine 1-yl group, 6-methoxymethylhexahydropyridazine 1 Group, 2-aminoethylhexahydropyridazine 1-yl group, 3 aminoethylhexahydropyridazine 1-yl group, 4 aminoethylhexahydropyridazine 1-yl group, 5 aminoethylhexahydropyridazine 1-yl group, 6 aminoethyl Oxahydropyridazine 1-yl group, 2 methylaminoethylhexahydropyridazine 1-yl group, 3-methylaminoethylhexahydropyridazine 1-yl group, 4 methylaminoethylhexahydropyridazine 1-yl group, 5 methylaminoethylhexahydride Pyridazine 1-yl group, 6-methylaminoethylhexahydropyridazine 1-yl group, 3 aminomethylhexahydride oral pyridazine 1-yl group, 4 aminomethylhexahydropyridazine 1-yl group, 5-aminomethylhexahydropyridazine 1-yl group 6-aminomethylhexahydropyridazine 1-yl group, 3-methylaminomethylhexahydropyridazine 1-yl group, 4-methylaminomethylhexahydropyridazine 1-yl group, 5 methylaminomethylhexahydride pyridazine 1-yl group, 6 methylaminomethylhexahydropyridazine 1-yl group, 3 dimethylaminomethylhexahydropyridazine 1-yl group, 4-dimethylaminomethylhexahydropyridazine 1-yl group, 5 dimethylaminomethylhexahydropyridazine Gin 1-yl group, 6 dimethylamine Nomethylhexahydropyridazine 1-yl group, 2 Dimethylaminoethylhexahydropyridazine 1-yl group, 3 Dimethylaminoethylhexahydropyridazine 1-yl group, 4-dimethylaminoethylhexahydropyridazine 1-yl group, 5 Dimethylamino Ethylhexahydropyridazine 1-yl group, 6-dimethylaminoethylhexahydropyridazine 1-yl group;

Hexahydropyrimidine 1-yl group, 2 oxohexahydropyrimidine 1-yl group, 4 oxohexahydropyrimidine 1- 1 group, 5 hexohexahydropyrimidine 1- 1 group, 6 oxohexahydropyrimidine 1- 1 group 2-methylhexahydropyrimidine 1-yl group, 3-methylhexahydropyrimidine 1-yl group, 4-methylhexahydropyrimidine 1-yl group, 4-methylhexahydropyrimidine 1-yl group, 2, 2 Dimethylhexahydropyrimidine 1-yl group, 4, 4-dimethylhexahydropyrimidine 1-y Group, 5, 5 dimethylhexahydropyrimidine 1-yl group, 6, 6 dimethylhexahydride oral pyrimidine- 1-yl group, 2 hydroxymethylhexahydropyrimidine-1-yl group, 4-hydroxymethylhexa 1-yl group of hydropyrimidine, 5-hydroxymethylhexahydride oral pyrimidine- 1-yl group, 6-hydroxymethylhexahydropyrimidine-1-yl group, 2-force rubamoylhexahydropyrimidine 1-yl group, 3-force rubamoyl Xahydropyrimidine 1-yl group, 4 1-strength rubamoylhexahydropyrimidine 1-yl group, 5 Carbamoylhexahydropyrimidine 1-l group, 6-force rubamoylhexahydropyrimidine 1-yl group, 2-methylcarbamoylhexahydropyrimidine 1-yl group, 3-methyl-powered ruberamoylhexahydropyrimidine 1-yl group, 4-methylcarbamoylhexahydryl pyrimidine— 1-yl group, 5-methylcarbamoylhexahydropyrimidine— 1-yl group, 6-methylcarbamoylhexahydropyrimidine 1-yl group, 2 dimethylcarbamoylhexahydropyrimidine— 1-yl group, 3 dimethylcarbamoylhexahydropyrimidine 1-yl group, 4 dimethylcarbamoylhexahydropyrimidine 1-yl group, 5-dimethylcarbamoylhexahydropyrimidine 1-yl group, 6-dimethylcarbamoylhexahydropyrimidine 1-yl group , 3-methoxymethylhexahydropyrimidine 1-yl group, 4-methoxymethylhexahydropyrimidine 1-yl group, 5-methoxymethylhexahydropyrimidine 1-yl group, 6-methoxymethylhexahydropyrimidine 1-yl group 2 groups Noethylhexahydropyrimidine 1-yl group, 3 Aminoethylhexahydropyrimidine 1-yl group, 4 Aminoethylhexahydropyrimidine 1-yl group, 5 Aminoethylhexahydropyrimidine 1-yl group, 6 Aminoethyl Hexahydropyrimidine 1-1yl group, 2-methylaminoethylhexahydropyrimidine 1-yl group, 3-methylaminoethylhexahydropyrimidine 1-yl group, 4-methylaminoethylhexahydropyrimidine 1-yl group, 5-methylaminoethyl Oxahydropyrimidine 1-yl group, 6-methylaminoethylhexahydropyrimidine 1-yl group, 2-dimethylaminoethylhexahydropyrimidine 1-yl group, 3 dimethylaminoethylhexahydropyrimidine 1-yl group, 4-Dimethylaminoethylhexahydropyrimimi Gin-1-yl group, 5-dimethylaminoethylhexahydropyrimidine 1-yl group, 6-dimethylaminoethylhexahydropyrimidine-1-yl group; Homopiperazino, 2-oxohomopiperazino, 3-oxohomopiperazino, 5-oxohomopiperazino, 6 oxohomopiperazino, 7 oxohomopiperazino, 2-oxo 4 Methylhomopiperazino group, 3-oxo 4 Methylhomopiperazino group, 5-Oxo 4 Methylhomopiperazino group, 6-Oxo 4 Methylhomopiperazino group, 7-Oxo4 Methylhomopipe Ladino group, 2, 3 Dioxohomopiperazino group, 2,7 Dioxohomopiperazino group, 3,5-Dioxohomopiperazino group, 3,7-Doxohomopiperazino group, 2 , 3 Dioxo4 Methylhomopiperazino group, 2,7 Dixo4 Methylhomopiperazino group, 3,5-Dioxo4 Methylhomopiperazino group, 3,7-Doxo4-methylhomopiperazino group, 2 Methyl Homopiperazino group, 3 Methylhomopiperazino group, 4 Methyl homopiperazino group, 5-methylhomopiperazino group, 6-methylhomopiperazino group, 7 Methylhomopiperazino group, 2 ethylhomopiperazino group, 3 ethylhomopiperazino group, 4 Ethylhomopiperazino group, 5-Ethylhomopiperazino group, 6-Ethylhomopiperazino group, 7-Ethylhomopiperazino group, 4-Cyclopropylhomopiperazino group, 2,2-Dimethylhomo Piperazino group, 3,3-Dimethylhomopiperazino group, 5,5-Dimethylhomopiperazino group, 6,6 Dimethylhomopiperazino group, 7,7 Dimethylhomopiperazino group, 2,3 Dimethylhomopipe group Ladino group, 2,4 Dimethylhomopiperazino group, 3,4 Dimethylhomopiperazino group, 3,5-Dimethylhomopiperazino group, 3,4,5-Trimethylhomopiperazino group, 2 Hydroxymethylhomo Piperazino group, 3-hydroxymethy Homopiperazino group, 5-hydroxymethyl homopiperazino group, 6-hydroxymethyl homopiperazino group, 7-hydroxymethyl homopiperazino group, 2 hydroxymethyl-4 methylhomopiperazino group, 3-hydroxymethyl 4-methylhomopiperazino group, 5-hydroxymethyl 4-methylhomopiperazino group, 6-hydroxymethyl- 4-methylhomopiperazino group, 7-hydroxymethyl 4-methylhomopiperazino group, 2-methoxymethylhomopiperazi group Group, 3-methoxymethyl homopiperazino group, 5-methoxymethyl homopiperazino group, 6-methoxymethyl homopiperazino group, 7-methoxymethyl homopiperazino group, 2-methoxymethyl-4-methylhomopiperazino group Group, 3-methoxymethyl-4-methyl homopiperazino group, 5-methoxymethyl-4-methyl Piperazino group, 6-methoxymethyl -4-methyl homo piperazino group, 7- main Tokishimechiru 4 methylhomopiperazine piperazino group, 2-hydroxy E chill homo piperazino group, 3 -Hydroxyethyl homopiperazino group, 4-hydroxyethyl homopiperazino group, 5-hydroxyethyl homopiperazino group, 6-hydroxyethyl homopiperazino group, 7-hydroxyethyl homo Piperazino group, 2 Hydroxyethyl 4 Methylhomopiperazino group, 3 Hydrochichetyl 4 Methylhomopiperazino group, 5-Hydroxyethyl 4 Methylhomopiperazino group, 6-Hydroxyethyl-4 methylhomopiperazino Group, 7-hydroxyethyl-4-methyl homopiperazino group, 2-methoxyethyl homopiperazino group, 3-methoxyethyl homopiperazino group, 4-methoxyethyl homopiperazino group, 5-methoxyethyl homopiperino group Perazino group, 6-methoxyethyl homopiperazino group, 7-methoxyethyl homopiperazino group, 2-methoxyethyl-4-methyl homopipe Dino group, 3-methoxyethyl 4-methyl homopiperazino group, 5-methoxyethyl 4-methyl homopiperazino group, 6-methoxyethyl 4-methyl homopiperazino group, 7-methoxyethyl 4-methyl homopiperazino group, 2-force rubamoyl homo Piperazino group, 3-force rubamoyl homopiperazino group, 4 1-strength rubamoyl homopiperazino group, 5-force rubamoyl homopiperazino group, 6-force rubamoyl homopiperazino group, 7-force rubamoyl Homopiperazino group, 2-force rubermoyl 4-methylhomopiperazino group, 3-force rubermoyl 4-methylhomopiperazino group, 4-strength ruvamoyl homopiperazino group, 5-strength rubermoyl-4 methylhomopiperazino group, 6-force rubamoyl 4-methyl homopiperazino group, 7-force rubamoyl 4-methyl homopiperazino group, 2-methylcarbamoyl Homopiperazino group, 3-methylcarbamoyl homopiperazino group, 4 methylcarbamoyl homopiperazino group, 5-methylcarbamoyl homopiperazino group, 6-methylcarbamoyl homopiperazino group, 7-methylcarbamoyl homopiperazino group Razino group, 2 Methylcarbamoyl 4 Methylhomopiperazino group, 3-Methylcarbamoyl 4 Methylhomopiperazino group, 5-Methylcarbamoyl-4 Methylhomopiperazino group, 6-Methylcarbamoyl 4 Methylhomopiperazino group, 7 —Methylcarbamoyl 4 methylhomopiperazino group, 2 dimethylcarbamoylhomopiperazino group, 3 dimethylcarbamoylhomopiperazino group, 4 dimethylcarbamoylhomopiperazino group, 5-dimethylcarbamoylhomopiperazino group, 6-dimethylcarbamoylhomopiperazino group 7—Zime Rukaruba moil Homo piperazino group, 2-dimethylcarbamoyl -4-methyl homo piperazino group, 3-dimethylcarbamoyl-4-methyl-homo piperazino group, 5- dimethylcarbamoyl 4 Methylhomopiperazino group, 6-dimethylcarbamoyl 4-Methylhomopiperazino group, 7 Dimethylcarbamoyl-4 Methylhomopiperazino group, 2—Strengthyl valamoylmethyl homopiperazino group, 3—Strength rubamoyl methyl homo Piperazino group, 4 strong rubamoylmethyl homopiperazino group, 5-strong rubamoylmethyl homopiperazino group, 6-strong rubamoylmethyl homopiperazino group, 7-strong rubamoylmethyl homopiperazino group, 2 —Strong rubamoylmethyl 4-methylhomopiperazino group, 3—Strengthened ruberamoylmethyl 4 methylhomopiperazino group, 5—Strengthened ruberamoylmethyl—4 methylhomopiperazino group, 6—Strengthened ruberamoylmethyl 4-methylhomopiperazino group, 7-strength rubamoylmethyl 4-methylhomopiperazino group, 2-methylcarbamoylmethylhomopiperazino group, 3-methylcarba Ilmethyl homopiperazino group, 4-methylcarbamoyl homopiperazino group, 5-methylcarbamoyl homopiperazino group, 6-methylcarbamoyl homopiperazino group, 7-methylcarbamoyl homopiperazino group, 2-methylcarbamoylmethyl-4-methylhomopiperazino Group, 3-methylcarbamoylmethyl-4 methylhomopiperazino group, 5-methylcarbamoyl-4 methylhomopiperazino group, 6-methylcarbamoyl-4 methylhomopiperazino group, 7-methylcarbamoyl4 methylhomopipe Radino group, 2 dimethylcarbamoylmethyl homopiperazino group, 3-dimethylcarbamoylmethyl homopiperazino group, 4 dimethylcarbamoylmethyl homopiperazino group, 5-dimethylcarbamoylmethyl homopiperazino group, 6-dimethyl Carbamoylmethylho Piperazino group, 7-dimethylcarbamoyl methyl homopiperazino group, 2 dimethylcarbamoylmethyl 4 methylhomopiperazino group, 3-dimethylcarbamoylmethyl-4 methylhomopiperazino group, 5-dimethylcarbamoylmethyl 4 methylhomopiperazi Group, 6-dimethylcarbamoylmethyl 4-methylhomopiperazino group, 7-dimethylcarbamoylmethyl-4 methylhomopiperazino group, 2-aminomethylhomopiperazino group, 3-aminomethylhomopiperazino group, 5-amino Methyl homopiperazino group, 6-aminomethyl homopiperazino group, 7-aminomethyl homopiperazino group, 2 aminomethyl-4 methylhomopiperazino group, 3 aminomethyl-4-methylhomopiperazino group, 5-aminomethyl-4-methylhomopiperazino group, 6-aminomethyl 4-methylphospho Piperazino group, 7-aminomethyl -4-methyl homo piperazino group, 2-methyl § amino methyl homo piperazino group, 3-methyl § amino methyl homo piperazino group, 4-main Tyraminomethyl homopiperazino group, 5-methylaminomethyl homopiperazino group, 6-methylaminomethyl homopiperazino group, 7-methylaminomethyl homopiperazino group, 2 methylaminomethyl 4-methylhomopiperazino group, 3-methylaminomino 4-methylhomopiperazino group, 5-methylaminomethyl- 4-methylhomopiperazino group, 6-methylaminomethyl 4-methylhomopiperazino group, 7-methylamino Methyl 4 Methyl homopiperazino group, 2 Dimethylaminomethyl homopiperazino group, 3 Dimethylaminomethyl homopiperazino group, 4-Dimethylaminomethyl homopiperazino group, 5-Dimethylaminomethyl homopiperino group Perazino group, 6-dimethylaminomethyl homopiperazino group, 7-dimethylaminomethyl homopiperazino group, 2 Dimethylaminomethyl-4 Tylhomopiperazino group, 3 Dimethylaminomethyl 4 Methylhomopiperazino group, 5-Dimethylaminomethyl 4 Methylhomopiperazino group, 6-Dimethylaminomethyl-4 Methylhomopiperazino group, 7-Dimethylaminomethyl-4 methylhomo Piperazino group, 2 aminoethyl homopiperazino group, 3 aminoethyl homopiperazino group, 4 aminoethyl homopiperazino group, 5-aminoethyl homopiperazino group, 6 aminoethyl homopiperazino group 7-aminoethyl homopiperazino group, 2-aminoethyl 4-methyl homopiperazino group, 3-aminoethyl 4-methyl homopiperazino group, 5-aminoethyl-4 methylhomopiperazino group, 6-aminoethyl-4-methylhomopiperazino group, 7 Aminoethyl-4 methyl homopiperazino group, 2-methylaminoethyl homopiperazin Group, 3-methylaminoethyl homopiperazino group, 4-methylaminoethyl homopiperazino group, 5-methylaminoethyl homopiperazino group, 6-methylaminoethyl homopiperazino group, 7 methylaminoethyl Homopiperazino group, 2-methylaminoethyl 4 Methylhomopiperazino group, 3-Methylaminoethyl 4 Methylhomopiperazino group, 5-Methylaminoethyl-4 Methylhomopiperazino group, 6-Methylaminoethyl 4 Methylhomo Piperazino group, 7-methylaminoethyl-4 methyl homopiperazino group, 2 dimethylaminoethyl homopiperazino group, 3 dimethylaminoethyl homopiperazino group, 4-dimethylaminoethyl homopiperazino group, 5-dimethylaminoethyl homopiperazino group, 6-dimethylaminoethyl homopiperazino group, 7-dimethylamino Echiruhomopi Perajino group, 2-dimethylaminoethyl -4-methyl-homo piperazino group, 3 dimethylaminopyridine aminoethyl 4-methyl homo piperazino group, a 5-dimethylaminoethyl 4 Mechiruhomopi Perazino group, 6-dimethylaminoethyl-4 methylhomopiperazino group, 7-dimethylaminoethyl-4 methylhomopiperazino group, 4 methanesulfol homopiperazino group, 4 methanesulfo-laminohomopiperazino group, 4 (azetidine 1 Yl) homopiperazino group, 4 pyrrolidinohomopiperazino group, 4-piperidinohomopiperazino group;

 [0069] A 1,4-oxazepane-4-yl group and the like can be given as representative examples.

 Of these, the following are preferred.

 Azetidine 1-yl group, 3 Dimethylaminoazetidine 1-yl group, 2-Methylazetidine 1-yl group, 3 Methylazetidine 1-yl group, 2, 2 Dimethylazetidine 1-yl group, 3, 3 Dimethylazetidine 1-yl group, 2, 2 Dimethyl-3 dimethylaminoazetidine 1-yl group, 2 Hydroxymethylazetidine 1-yl group, 3-Hydroxymethylazetidine 1-yl group, 2-Strength rubamoylazetidine 1-yl group, 2-Methylcarbamoyl Zetidine 1-yl group, 2-dimethylcarbamoylazetidine 1-yl group, 3, 3 difluoroazetidine 1-yl group;

 [0071] pyrrolidino group, 2-methylpyrrolidino group, 2-aminomethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 2-methoxymethylpyrrolidino group, 2-fluoromethylpyrrolidino group, 2-trifluoro Methyl pyrrolidino group, 2, 2 dimethyl pyrrolidino group, 2, 5 dimethyl pyrrolidino group, 2-force rubamoyl pyrrolidino group, 2-methoxypyrrolidino group, 2-oxopyrrolidino group, 2-methoxymethyl-5-methyl Pyrrolidino group, 3-methylpyrrolidino group, 3-methoxymethylpyrrolidino group, 3-fluoromethylpyrrolidino group, 3-trifluoromethylpyrrolidino group, 3-aminopyrrolidino group, 3, 3-dimethylpyrrolidino group Group, 3-hydroxymethylpyrrolidino group, 3-strong rubamoylpyrrolidino group, 3-methoxypyrrolidino group, 3-fluoropyrrolidino group, 3, 3— Difluoropyrrolidino group;

 [0072] imidazolidine 1-yl group, 3-methylimidazolidine 1-yl group, 2-oxoimidazolidine 1-yl group, 4-oxoimidazolidine 1-yl group, 3-methyl 2-oxomidylidine 1 —Yl group, 3-methyl 4-oxoimidazolidine 1-yl group, 2,2-dimethylimidazoline 1-yl group;

[0073] Virazolidine mono-1-yl group, 2-methyl virazolidin mono-1-yl group, 3-oxovirazolidin monoyl group, 2-formyl-pyrazolidine monoyl group, 2-methylsulfol pyra Zolidine 1-yl group;

 [0074] piperidino group, 2-oxopiperidino group, 3-oxopiperidino group, 4-oxopiperidino group, 2 hydroxymethylpiperidino group, 3 hydroxymethylpiperidino group, 4-hydroxymethylpiperidino group, 2-methoxypiperidino group Group, 3-methoxypiperidino group, 4-methoxypiperidino group, 2-methylbiperidino group, 3-methylbiperidino group, 4-methylbiperidino group, 2,2 dimethylbiperidino group, 3,3 dimethylbiperidi Group, 4, 4 dimethylbiperidino group, 3-fluoropiperidino group, 4 fluoropiperidino group, 4 chloropiperidino group, 3, 3 difluoropiperidino group, 4, 4-difluoropi Peridino group, 2 Fluoromethylpiperidino group, 3-Fluoromethylpiperidino group, 4 Fluoromethylpiperidino group, 3, 3-Dichloropiperidino group, 4, 4 Dichloropiperidino group, 2 hydroxymethylpiperidino group, 2 rubamoylbiperidino group, 2-methylcarbamoylbiperidino group, 2-dimethylcarbamoylbiperidino group, 2-methoxymethylbiperidino group Group, 4-methyl-4-methoxypiperidino group, 2-aminomethylbiperidino group, 2-methylaminomethylbiperidino group, 2-dimethylaminomethylbiperidino group, 2-aminoethylpiperidino group, 2- Methylaminoethylpiperidino group, 2-dimethylaminoethylpiperidino group, 2-aminocyclopropylpiperidino group;

[0075] Piperazino group, 2-oxo 4-methylbiperazino group, 3-oxo 4-methylbiperazino group, 3-oxo 4-ethyl biperazino group, 4 formylpiperazino group, 2, 3 dioxo 4- Methylbiperazino group, 3,5 dixo 4-methylbiperazino group, 2,6 dixo 4-methylbiperazino group, 4-methylbiperazino group, 4-ethylbiperazino group, 4- Isopropylpiperazino group, 4-cyclopropylpiperazino group, 2,4 dimethylbiperazino group, 3,4 dimethylbiperazino group, 2 ethyl-4-methylbiperazino group, 3 ethyl 4-methyl Biperazino group, 2 isopropyl-4-methylbiperazino group, 3 isopropyl 4-methylbiperazino group, 2 cyclopropyl-4-methylbiperazino group, 3 cyclopropyl mono 4-methylbiperazino group, 3, 4, 5 Trimethylbiperazino group, 2, 2,4 trimethylpiperazino group, 3,3,4-trimethylbiperazino group, 3,3,4-trimethyl 5-oxopiperazino group, 2,2,4 trimethyl 3-oxopiperazino group, 2-hydroxymethyl-4-methyl Biperazino group, 3-hydroxymethyl-4-methylbiperazino group, 2-methoxymethyl 4-methylbiperazino group, 3-hydroxymethyl-4-methylbiperazino group, 2-hydroxychetyl 4-methylbiperazino group, 3-hydroxyethyl 4-methylbiperazino group, 2-methoxyethyl-4-methylbiperazino group, 3 —Methoxyethyl 4-methylbiperazino group, 2-strength rubermoyl 4-methylbiperazino group, 3-strength rubermoyl 4-methylbiperazino group, 4-strength ruberamoylbiperazino group, 2-methylcarbamoyl 4-methylpiperazino group, 3-— Methylcarbamoyl 4-methylbiperazino group, 4-methylcarbamoylpiperazino group, 2 dimethylcarbamoyl 4-methylbiperazino group, 3 dimethyl strength rubamoyl 4-methylbiperazino group, 4 dimethylcarbamoylbiperazino group, 2— Strength ruvamoyl methyl 4-methylpiperazino group, 3-strength ruba Ilmethyl 4-methyl piperazino group, 4-strength rubamoylmethyl biperazino group, 2-methylcarbamoylmethyl- 4-methylbiperazino group, 3-methylcarbamoylmethyl- 4-methylbiperazino group, 4-methylcarbamoylpipe Ladino group, 2 dimethylcarbamoylmethyl-4-methylpiperazino group, 3 dimethylcarbamoylmethyl-4-methylbiperazino group, 2 aminomethyl 4-methylbiperazino group, 2 methylaminomethyl-4-methylbiperazino group 2 dimethylaminomethyl 4 methylbiperazino group, 2 aminoethyl 4 methylbiperazino group, 2 methylaminoethyl-4-methylbiperazino group, 2 dimethylaminoethyl-4 methylbiperazino group;

Morpholino group, 2 methylmorpholino group, 3 methylmorpholino group, 2 ethylmorpholino group, 3 ethinoremonoreforino group, 2, 2 dimethinoremonoreforino group, 3, 3 dimethinoremonoreforino group, 3— 4-methyl group, 3-hydroxymethylmorpholino group, 3-methoxymethylmorpholino group, 3-hydroxyethylmorpholino group, 3-methoxyethylmorpholino group, 3-force carbamoylmorpholino group, 3-methylcarbamoylmorpholino group , 3-dimethylcarbamoylmorpholino group, 3-force rubamoylmethylmorpholino group, 3-methylcarbamoylmethylmorpholino group, 3-dimethylcarbamoylmethylmorpholino group, 3-forcecarbamoylethylmorpholino group, 3-methylcarbamoylethylmorpholino Group, 3-dimethyl-powered rubermoylethyl morpho Group, 3-aminomethylmorpholino group, 3-methylaminomethylmorpholino group, 3-dimethylaminomethylmorpholino group, 3-aminoethylmorpholino group, 3-methylaminoethylmorpholino group, 3-dimethylaminoethylmorpholino group ; [0077] 2-acetyl-hexahydropyridazine 1-yl group, 2-formylhexahydropyridazine 1-yl group, 2-methylhexahydropyridazine 1-yl group, 3-oxohexahydropyridazine-1-yl group, 6 oxohexahydropyridazine 1-yl group, 2, 3 dimethylhexahydropyridazine 1-yl group, 3 hydroxymethylhexahydropyridazine 1-yl group, 5 hydroxymethylhexahydropyridazine 1-yl group, 6 hydroxymethylhexahexyl Hydropyridazine 1-yl group, 2-force rubamoylhexahydropyridazine 1-yl group, 2-methylcarbamoylhexahydropyridazine 1-yl group, 2-dimethylcarbamoylhexahydropyridazine 1-yl group;

 [0078] 2-oxohexahydropyrimidine 1-yl group, 4-oxohexahydropyrimidine 1-yl group, 6-oxohexahydropyrimidine 1-yl group, 2-methylhexahydropyrimidine 1-yl group, 3-methylhexa Hydropyrimidine 1-yl group, 3-force rubamoylhexahydropyrimidine 1-yl group, 3-methylcarbamoylhexahydropyrimidine 1-yl group, 3 dimethylcarbamoylhexahydropyrimidine 1-yl group, 6 hydroxymethylpyrimidine-1 —Yil group;

[0079] 2 oxo 4 methyl homopiperazino group, 3 oxo 4 methyl homopiperazino group, 5 oxo 4 methyl homopiperazino group, 6-oxo 4 methyl homopiperazino group, 7 oxo 4 methyl homopiperino group Razino group, 2,3 dioxohomopiperazino group, 2,7 dioxohomopiperazino group, 3,5-dioxohomopiperazino group, 3,7-doxohomopiperazino group, 2, 3 Dioxo 4 Methyl homopiperazino group, 2, 7 Dioxo 4-methyl homopiperazino group, 3, 5-Dioxo 4 Methyl homopiperazino group, 3, 7-Dioxo 4 Methyl homopiperazino group, 4 Methyl homo Piperazino group, 4-ethyl homopiperazino group, 4-cyclopropylhomopiperazino group, 2,4 dimethylhomopiperazino group, 3,4-dimethyl homopiperazino group, 3, 4, 5 trimethylhomo Piperazino group, 2 hydroxymethyl 4 Tylhomopiperazino group, 7-hydroxymethyl 4-methylhomopiperazino group, 2-methoxymethyl-4-methylhomopiperazino group, 3-methoxymethyl-4-methylhomopiperazino group, 5-methoxymethyl-4-methylhomo Piperazino group, 6-methoxymethyl 4-methylhomopiperazino group, 7-methoxymethyl-4 methylhomopiperazino group, 2-hydroxyethyl 4 methylhomopiperazino group, 7-hydroxyethyl 4 methylhomo Piperazino group, 2-methoxyethyl-4-methylhomopiperazino group, 3-methoxyethyl-4-methylhomopiperazino group, 5-methoxyethyl-4-methylhomopiperazino group, 6-methoxetyl 4-methylhomopiperazino group, 7- Methoxyethyl 4 Methylhomopiperazino group, 2—Mermopiperazino group 4 Methylhomopiperazino group, 7—Mervaylmoyl 4-group Methylhomopiperazino group, 2-Methylcarbamoyl 4 Methylhomopiperazino group, 7—Methyl Rucarbamoyl 4 methyl homopiperazino group, 2 dimethylcarbamoyl homopiperazino group, 7 dimethylcarbamoyl homopiperazino group; 1,4-oxazepan 4-yl group; 3 methyl 4-oxoimidazolidine 1-yl group.

 Of these, the following are more preferable.

 Azetidine 1-yl group, 3 dimethylamino azetidine 1-yl group, 2, 2 dimethyl 3 dimethylamino azetidine 1-yl group, 2 hydroxymethylazetidine 1-yl group, 2-force rubamoylazetidine 1-yl group, 2-methylcarbamoylazetidine 1-yl group, 2-dimethylcarbamoylazetidine 1-yl group; pyrrolidino group, 2-methylpyrrolidino group, 2-aminomethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 2 —Methoxymethylpyrrolidino group, 2-Fluoromethylpyrrolidino group, 2-Trifluoromethylpyrrolidino group, 2,2 Dimethylpyrrolidino group, 2,5 Dimethylpyrrolidino group, 2-Strong rumoylpyrrolidino group, 2-Methoxypyrrolyl Dino group, 2-oxopyrrolidino group, 2-methoxymethyl 5-methylpyrrolidino group, 3-methylpyrrolidi Group, 3-methoxymethylpyrrolidino group, 3 fluoromethylpyrrolidino group, 3-trifluoromethylpyrrolidino group, 3-aminopyrrolidino group, 3-hydroxymethylpyrrolidino group, 3-force rubamoylpyrrolidino group , 3-methoxypyrrolidino group, 3-fluoropyrrolidino group, 3,3-difluoropyrrolidino group;

[0081] imidazolidine 1-yl group, 3-methylimidazolidine 1-yl group, 2 oxoimidazolidine 1-yl group, 4-oxoimidazolidine 1-yl group, 3-methyl 2-oxomidylidine 1 —Yl group, 3-methyl 4-oxoimidazolidine 1-yl group, 2,2-dimethylimidazoline 1-yl group; virazolidine 1-yl group, 2-methyl-virazolidine 1-yl group, 2-— Formyl-pyrazolidine 1-yl group, 2-methylsulfo-pyrazolidine 1-yl group; piperidino group, 2-oxopiperidino group, 2-methoxypiperidino group, 3-methoxypiperidino group, 4-methoxypiperidino group , 2 Hydroxymethylpiperidino group, 2 One strength rubamoyl biperidino group, 2-methylcarbamoyl biperidino group, 2-dimethylcarbamoyl biperidino group, 2-methoxymethyl biperidino group, 2-aminomethyl biperidino group, 2-methylamino Methylbiperidino group, 2-dimethylaminomethylbiperidino group, 2-aminoethylbiperidino group, 2-methylaminoethylpiperidino group, 2-dimethylaminoethylpiperidino group, 3-fluoropiperidino group, 4 fluoropiperidino group, 4-methylbiperidino group, 4-methoxypiperidino group, 3,3-difluoropiperidino group, 4,4-difluoropiperidino group, 3-fluoro Romethylpiperidino group, 4 Fluoromethylpiperidino group, 4 Methyl 4-methoxypiperidino group, 2 Aminocyclopropylpiperidino group; Piperazino group, 2--oxo 4-methylbiperazi Group, 3-oxo-4-methylbiperazino group, 3-oxo-4-ethylbiperazino group, 4 formylpiperazino group, 2, 3 dixo 4-methylbiperazino group, 3, 5 dioxo 4-methylbibenzo Perazino group, 2, 6 Dioxo 4-methylpiperazino group, 4-methylbiperazino group, 4-ethylbiperazino group, 4 isopropylpiperazino group, 4-cyclopropylpiperazino group, 2, 4 Dimethylbiperazino group, 3,4 Dimethylpiperazino group, 2 ethyl 4-methylbiperazino group, 3 ethyl-4-methylbiperazino group, 3, 4, 5 Trimethylbiperazino group, 2, 2, 4 Trimethylbipera Dino group, 3, 3, 4 trimethylpiperazino group, 3, 3, 4 trimethyl 5-oxopiperazino group, 2, 2, 4 trimethyl-3-oxopiperazino group, 2 hydroxymethyl-4-methylbiperazino group 3 Hydroxymethyl 4-methylbiperazino group, 2-methoxymethyl 4-methylpiperazino group, 3-methoxymethyl-4-methylbiperazino group, 2-hydroxyethyl 4-methylbiperazino group, 3-hydroxyethyl 4-methylbiperazino group, 2-methoxyethyl 4-methylbiperazino group, 3-methoxyethyl 4-methylbiperazino group, 2-force rubamoyl 4-methylbiperazino group, 2-methylcarbamoyl 4-methylbiperazino group, 2 dimethylcarbamoyl 4-methylpiperazino group, 2 force Rubamoylmethyl 4 methyl piperazino group, 2-methylcarbamoylmethyl-4-methylbiperazino group, 2 dimethyl-force rubamoylmethyl 4 methylbiperazino group, 2 aminomethyl 4 methylbiperazino group, 2 methylaminomethyl-4-methylbiperazino group, 2 Dimethylaminomethyl 4-me Rubiperajino group, 2-aminoethyl over 4-methyl-bi Pella Gino group, 2 Mechiruaminoe chill 4 Mechirubiperajino group, 2-dimethylaminoethyl 4 Mechirubiperajino group; [0082] Morpholino group, 2, 2 dimethylmorpholino group, 3, 3 dimethylmorpholino group, 3 methylmorpholine-4-yl group, 3-hydroxymethylmorpholino group, 3-methoxymethylmorpholino group, 3-hydroxyethylmorpholino group 3-methoxyethylmorpholino group, 3-carbamoylmorpholino group, 3-methylcarbamoylmorpholino group, 3-dimethylcarbamoylmorpholino group, 3-aminomethylmorpholino group, 3-methylaminomethylmorpholino group, 3 -Dimethylaminomethylmorpholino group, 3-aminoethylmorpholino group, 3-methylaminoethyl morpholino group, 3 dimethylaminoethylmorpholino group; 2 acetylhexahydropyridazine 1-yl group, 2 formylhexahydropyridazine 1-yl group, 3 Oxohexahydropyridazine 1-yl group 2-methylhexahydropyridazine 1-yl group,

2—force rubamoyl hexahydropyridazine 1-yl group; 2-oxohexahydropyrimidine 1-yl group, 4-oxohexahydropyrimidine 1-yl group, 3-methylhexahydryl pyrimidine 1-yl group, 6 1-yl group of hydroxymethylhexahydropyrimidine; 2 oxo 4 methyl homopiperazino group, 3 oxo 4 methyl homopiperazino group, 5 oxo 4 methyl homopiperazino group, 7 oxo 4 methyl homopipe group Lazino group, 2,

3 Dioxo 4 Methyl homopiperazino group, 2, 7 Dioxo 4 Methyl homopiperazino group, 3, 5-Doxo 4 Methyl homopiperazino group, 3, 7-Dioxo 4 Methyl homopiperazino group, 4 Methyl homopiperazino group, 4-ethyl homopiperazino group, 4-cyclopropyl homopiperazino group; 1,4-oxazepanyl 4-yl group; 3 methyl 4-oxoimidazolidine 1-yl group.

 Of these, the following are particularly preferable.

3 Dimethylaminoazetidine 1-yl group, 2, 2 Dimethyl-3 Dimethylaminoazetidine 1-yl group, 2-Hydroxymethylazetidine 1-yl group, 2-Force Lubamoylazetidine 1-yl group; Pyrrolidino group, 2-Methylpyrrolidino Group, 2-fluoromethylpyrrolidino group, 2-trifluoromethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 2,5 dimethylpyrrolidino group, 2-force rubamoylpyrrolidino group, 3 fluoropyrrolidino group 3,3 difluoropyrrolidino group; virazolidino group, 2-methyl-pyrazolidine 1-yl group, 2-formyl-virazolidine 1-yl group, 2-methylsulfo-lazolazole 1-yl group; piperidino Group, 2-hydroxymethylpiperidino group, 2-force rubamoyl biperidino 2-methylcarbamoylbiperidino group, 2-dimethylcarbamoylbiperidino group, 3-methoxypiperidino group, 3-fluoropiperidino group, 4 fluoropiperidino group, 4-methylbiperidino group, 4 -Methoxypiperidino group, 3,3-difluoropiperidino group, 4,4-difluoropiperidino group, 4 fluoromethylpiperidino group, 4-methyl-4-methoxypiperidino group, 2 aminocyclopropylpiperidino group ; 3-oxo 4-methylbiperazino group, 3-oxo 4-ethyl biperazino group, 4-methyl biperazino group, 4-ethyl biperazino group, 4-isopropyl piperazino group, 4-cyclopropyl Piperazino group, 2, 4 Dimethylbiperazino group, 3,4-Dimethinoleviperazino group, 3, 4, 5 Trimethinoleviperazino group, 2, 2, 4 — Trimethylbiperazino group, 3, 3 , 4-trimmer Rubiperazino group; morpholino group, 3-methylmorpholine 4-yl group, 3-force rubamoylmorpholino group; thiomorpholino group, 1,1-dioxothiomorpholino group; 2 methylhexahydropyridazine 1-yl group, 3 methyl Xahydropyridazine 1yl group; 3 oxo 4 methyl homopiperazino group, 5-oxo 4 methyl homopiperazino group, 4 methyl homopiperazino group, 4 ethylhomopiperazino group, 4-cyclopropyl homopipe group Razino group; 1,4-Oxazepane 4-yl group; 3-Methyl-4-oxoimidazolidine 1-yl group; 2 Acetylhexahydropyridazine 1-yl group, 2-Streptylhexahydropyridazine 1-yl group .

 Of these, the following are most preferred.

2-methylpyrrolidino group, 2,5-dimethylpyrrolidino group, 2-fluoromethylpyrrolidino group, 2-trifluoromethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 2-methoxymethyl-5-methylpyrrolidino group , 2-force rubamoylpyrrolidino group, 3 fluoropyrrolidino group, 3, 3 difluoropyrrolidino group; 2-methyl-pyrazolidine 1-yl group, 2 formyl-birazolidino group, 2-methylsulfo-pyrazolidine 1-yl group Piperidino group, 3-methoxypiperidine 1-yl group, 3 fluoropiperidino group, 4-methylbiperidino group, 4-methoxypiperidino group, 4 fluoropiperidino group, 4, 4-difluoro Lopiperidino group, 2 aminocyclopropylpiperidino group; 3 oxo-4-methylbiperazino group, 3-oxo-4-ethylbiperazino group, 4-methylbipera group Amino group; to hexa hydro pyridazine -1-I le group; a morpholino group, 3-methylmorpholine -4 Iru group; 1, 4 Okisazepan 4-I le group. [0085] As the salt of the compound (I) of the present invention, not all of the compounds of the present invention form a salt.

 1 2

 In such cases, a salt is formed. In addition, the salts may form solvates. The salt here refers to a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid; a salt of an organic acid such as methanesulfonic acid, ptoluenesulfonic acid, fumaric acid or trifluoroacetic acid; And salts with alkali metal or alkaline earth metal ions such as calcium.

 [0086] The solvate in the solvate of the compound (I) or a salt thereof of the present invention absorbs moisture in the air in addition to the solvate added with the solvent used for crystallization of crystals. Including those formed. Examples of the solvent include water, lower alcohols such as methanol and ethanol, and organic solvents such as acetone and acetonitrile.

[0087] Among the compounds (I) of the present invention, as a more preferable compound that strongly suppresses platelet aggregation without inhibiting COX-1 and COX-2, 4- [1- ( 6-methoxy-3 pyridyl) -5- (1-methyl-1H pyrazole-4-yl) -1H pyrazole-3 carbo] morpholine, 1- [1— (6-methoxy-3-pyridyl)-5- (1— Methyl 1H—imidazole-4-yl) 1H pyrazole-3 carbo] -4-methoxypiberidine, 1— [1— (6-methyl-3-pyridyl) 5— (1-methyl——1H pyrrole 1-3— 1) 1H pyrazole-3 carbol] -4-methyl-3-oxopiperazine, 1- [1- (6-methoxy-3-pyridazil) -5- (1-methyl-1H pyrrole-3-yl) 1H-pyrazole- 3-carbol] —4-methyl-3-oxopiperazine, 1— [1— (6-methoxy-1-pyridyl) 5 — (Thiazole 4-yl) 1H Pyrazole 1-3-carbonyl] 4 Methyl 3-oxopiperazine, 1— [1- (6-Methoxy-1-pyridyl) -5- (Thiazole-4-yl) 1H Pyrazole-3 Carbo- 4] -Methylpiperazine, 1— [1— (6-Methoxy-3 pyridyl) -5- (thiazole-4-yl) —1H pyrazole-3-carbol] —4-methoxypiperidine, 1 — [1— (6-Methoxy-3 pyridyl) -5— (thiazole-4-yl) —1H Pyrazole-3-carbon] — 2—Strengthened rubermoyl biperidine, 1— [1— (6 —Methoxy— 3 pyridazil) —5— (thiazole-4 yl) 1H pyrazole-3 carbol] -4-methylpiperazine , 1- (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) -1H pyrazole-3-carbol] 4-methoxypiperidine, 1- [1- (6-methoxy 1-3 pyridazil) -5- (thiazole-4-yl) -1H pyrazole 3-carbol] -4,4 difluoropiperidine, 1- [1- (6-methoxy-1-pyridyl) 5— (1—Methyl-1H pyrazole-4-yl) 1H Pyrazole—3-carbol] hexahydropyridazine, 1— [1— (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) ) —1H —pyrazole-3-carbol] hexahydropyridazine, 4— [1— (6-methoxy-1-pyridyl) 5— (1-methyl 1H pyrazole-4-yl) 1H pyrazole 3-carbol ] — 1, 4-Oxazepane, 1— [1— (6-Methoxy-1-pyridyl) 5— (Thiazole-4-yl) —1H Razol-3-carbol] hexahydropyridazine, 4 — [1— (6-Methoxy-1-pyridyl) 5— (thiazole 4-yl) 1H pyrazolole 3—force norebonnole 1, 4-oxazepane, 1 [1 (6-Methoxy-3-pyridazil) -5- (1-Methyl-1H pyrazole-4-yl) -1H pyrazole-3-carbonyl] 4,4-difluoropiperidine, its salt or solvate thereof Can be mentioned. Of these, 4— [1— (6-methoxy-1-pyridyl) 5— (1-methyl 1H-virazole 4-yl) 1H-pyrazole-3 carbo] morpholine or 1— [1- (6-methoxy-1- 3 Pyridyl) 5- (1-Methyl 1H-imidazole 4-yl) 1H-pyrazole-3-carbonyl] -4-methoxypiperidine, its salts or their solvates are preferred.

 Of these, 4- [1— (6-methoxy-1-pyridyl) 5— (1-methyl 1H-virazol-4-yl) —1H pyrazole-3-carbol] morpholine, salt or solvent thereof The product exhibits a strong platelet aggregation inhibitory action without inhibiting COX-1 and COX-2, and is extremely superior as a pharmaceutical from the viewpoint of main drug efficacy, safety, oral absorption, and solubility. preferable.

 [0088] The compound (I) of the present invention can be produced by the following method. Hereinafter, representative production methods of the compound (I) of the present invention will be described.

[0089] [Chemical 5]

 (7)

(In the above formula, Ar and Ar are the same as defined above, and R ² represents a methyl group or ethyl.

 1 2

 A lower alkyl group such as a group is shown. )

 [0091] Compound (2) was treated by treating aromatic ketone (1) and oxalic acid dialkyl ester in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (sodium methoxide or sodium ethoxide). Obtainable. The reaction temperature is preferably 10 to 100 ° C.

 [0092] Compound (2) is obtained by dissolving or suspending compound (1) and dialkyl oxalate in an appropriate solvent such as N, N dimethylformamide and hydrogenating at -20 to 20 ° C under an argon stream. It can also be produced by reacting with sodium.

 [0093] Further, compound (2) is prepared by dissolving compound (1) in an inert solvent such as tetrahydrofuran, treating with a base such as lithium bis (trimethylsilyl) amide under cooling, and reacting with dialkyl ester oxalate. Can also be manufactured. The reaction temperature is preferably 78 to 20 ° C, particularly preferably -78 ° C.

 [0094] As the compound (1), a commercially available product may be used, or a compound produced by a method described in Reference Examples or a method according to the method may be used.

[0095] When the compound (1) has a functional group such as a hydroxyl group or an amino group, it is desirable to protect these functional groups with an appropriate protecting group in advance. Examples of the protecting group for the hydroxyl group include tert-butyl group, benzyl group, and the like. Examples of the protecting group for the amino group include trifluoroacetyl group, tert-butoxycarbol group, benzyloxycarboro group, benzene. And sulfo group and ρ-toluene sulfo group. These protecting groups are It can be deprotected under conditions suitable for the protecting group.

 [0096] Next, the compound (2) is dissolved in alcohol (methanol or ethanol), etc., and after adding the hydrazine derivative (4) or a salt thereof at room temperature, an appropriate amount of acetic acid is added and heated to reflux. Compound (5) can be produced. At that time, the regioisomer (6) is by-produced, but the desired compound (5) can be easily separated and purified by silica gel column chromatography or the like.

 [0097] The hydrazine derivative (4) or a salt thereof is obtained by dissolving an aromatic amine (3) in concentrated hydrochloric acid, adding sodium nitrite under ice-cooling to derive a diazo compound, and then using tin chloride (Π). It can be manufactured by processing. The reaction temperature is preferably −10 to 20 ° C.

 [0098] As the hydrazine derivative (4), a commercially available product or a method prepared by reacting hydrazine with a halogenated Ar as described in Reference Examples or a method according to the method may be used. The aromatic amine (3) may be a commercially available compound, or may be produced by the method described in Reference Examples or a method according to the method.

 [0099] In the above pyrazole ring formation reaction, acetic acid, triethylamine may be used in some cases where an appropriate amount of triethylamine, concentrated hydrochloric acid, p-toluenesulfonic acid, etc. may be added and heated to reflux instead of acetic acid. Compound (5) can be obtained without adding concentrated hydrochloric acid, p-toluenesulfonic acid, or the like.

 [0100] Various pyrazole derivatives (5) can be produced based on ordinary knowledge of organic chemistry. For example, the pyrazole derivative (5) has a 5- (1H-pi

 2

 (Roll 1) 1H The pyrazole derivative (5a) can be produced as shown below.

 [0101] [Chemical 6]

H.

[0102] (wherein Ar represents the same as above) [0103] The 5-aminovirazole compound (10) can be produced by adding a 1M hydrochloric acid ethanol solution at room temperature to an ethanol solution of the compound (9) and the hydrazine derivative (4) and heating to reflux. Compound (9) can be produced by suspending sodium ethoxide and oxalic acid jetyl ester in a suitable solvent such as tert-butyl methyl ether, adding acetonitrile (8) and heating to reflux. The compound (5a) can be produced by dissolving the compound (10) in a solvent such as acetic acid, adding 2,5 dimethoxytetrahydrofuran and heating to reflux.

 [0104] The above compound (5) can be derived into a carboxylic acid (7) by hydrolyzing an ester using a base, a Lewis acid or the like based on ordinary knowledge of organic chemistry. Examples of the base include hydroxides of alkali metals (for example, lithium, sodium, potassium, etc.). In addition, examples of the Lewis acid include boron tribromide. The reaction temperature is preferably −20 to: LOO ° C., particularly preferably 5 to 50 ° C.

 [0105] Further, the compound (5) can be converted into various derivatives by further modification based on ordinary knowledge of organic chemistry. For example, alcohol, triflate and nitrile derivatives (5c to e) can be produced from compound (5b).

 [0106] [Chemical 7]

 (5e)

(In the formula, Ar represents the same as described above, Bn represents a benzyl group, and R ² represents a lower alkyl group such as a methyl group or an ethyl group.)

[0108] Specifically, the benzyloxy compound (5b) was dissolved in ethanol or the like to obtain 10% palladium. Hydroxy compound (5c) can be produced by catalytic reduction using carbon as a catalyst. The triflate (5d) can be produced by dissolving the hydroxy compound (5c) in methylene chloride and reacting with trifluoromethanesulfonic anhydride at -50 to 50 ° C in the presence of a base such as pyridine. . Furthermore, the cyanate derivative (5e) can be produced by dissolving the triflate (5d) in 1,2-dichloroethane or the like and reacting it with cyanotri n-butyltin and tetrakis (triphenylphosphine) palladium (0). . The reaction temperature is preferably 10-100 ° C. The above reaction conditions, reagents and the like may be appropriately selected based on ordinary knowledge of organic chemistry.

 [0109] Further, as shown below, from the compound (5f), the carboxylic acid derivative (5g) is a diamine derivative.

 (5h) etc. can be manufactured.

 [0110] [Chemical 8]

[In the formula, Ar and R ² are the same as defined above, and Boc represents a tert-butoxycarbol group.]

 [0112] Specifically, the carboxylic acid derivative (5g) can be produced by dissolving methylbiazine derivative (5f) in pyridine and the like, adding selenium dioxide at room temperature, and then heating to reflux. Amine derivative (5h) can be produced by dissolving carboxylic acid derivative (5g) in 1,4-dioxane, etc., adding tert-butanol, triethylamine and diphenylphosphoryl azide at room temperature and then refluxing with heating. . The above reaction conditions, reagents, etc. should be selected appropriately based on general knowledge of organic chemistry.

 [0113] Further, the pyrazole derivative (5j) which is an Ar ^ -hydroxymethylpyrrolyl group has the following structure.

 2

 Can be manufactured as follows.

[0114] [Chemical 9]

 (1 2)

[In the above formula, 8 represents the same as above.]

 [0116] The hydroxymethyl derivative (¾) is prepared by dissolving 5-aminovirazole (10) in a solvent such as acetic acid and adding 2,5-dimethoxytetrahydro-3-furancarbaldehyde (12). The 3-formylpyrrolyl derivative (5i) can be produced by heating to reflux and further reduced with sodium borohydride. The hydroxymethyl group of the hydroxymethyl derivative (5j) thus obtained can be easily converted to a cyanomethyl group, an aminomethyl group or the like.

 [0117] As described above, the above-mentioned pyrazole derivative (5) can be converted into a carboxylic acid derivative (7) by hydrolyzing the ester.

[0118] The compound (I) of the present invention can be obtained by condensation of the carboxylic acid derivative (7) and the amine (13).

[0119] [Chemical 10]

 [In the formula, Ar and Ar are the same as defined above.]

 1 2

[0121] For the above condensation reaction, a method generally used as a peptide synthesis method may be applied. Examples of peptide synthesis methods include azide method, acid chloride method, acid anhydride method, DC C (dicyclohexylcarbodiimide) method, active ester method, carbodiimidazole method, DCCZHOBT (l-hydroxybenzotriazole) ) Method, using water-soluble carbodiimide And methods using Jetyl Cyanophosphate, such as M. Bodanszky, YS Klausner and MA Ondetti "Pepti de Snthesis (A Wiley-inter science publication, New York , l9 / o, GR Pettit 'Synthetic Peptides "(Elsevier Scientific Publication Company, New York, 1976), edited by The Chemical Society of Japan," 4th edition, Experimental Chemistry Course 22; Organic Synthesis IV "(Maruzen Corporation, 1992) etc. Examples of the solvent used in this condensation reaction include N, N-dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, and acetonitrile. The reaction temperature is preferably −20 to 50 ° C., more preferably 10 to 30 ° C. A commercially available compound may be used as the amine (13), and the method described in the literature can be used. The method described in the production example Ku is Yo be used those produced by the method according to these methods.

 [0122] In the above condensation reaction, when the amine body (13) has a functional group such as a hydroxyl group, an amino group, or a carboxyl group, these functional groups should be protected in advance using an appropriate protecting group. Is preferred. In the case of a hydroxyl group, tert-butyl group, benzyl group, etc. In the case of an amino group, in the case of a carboxyl group such as trifluoroacetyl group, tert-butoxycarbol group, benzyloxypolyol group, etc. What is necessary is just to use for a condensation reaction after derivatizing to methyl ester, tert-butyl ester or the like.

 [0123] The compound (I) of the present invention produced by the above method can be converted into a derivative of the compound (I) by further modification based on ordinary knowledge of organic chemistry. For example, alcohol, triflate, nitrile, and amide derivatives (Ib to Ie) can be obtained from compound (la).

[0124] [Chemical 11]

[0127] represents the same as described above, and Bn represents a benzyl group. )

 Specifically, alcohol (lb) can be produced by dissolving compound (la) in ethanol or the like and catalytically reducing it using 10% palladium-carbon as a catalyst. Trifler Hie) can be produced by dissolving alcohol (lb) in methylene chloride and reacting with trifluoromethanesulfonic anhydride at −50 to 50 ° C. in the presence of a base such as pyridine. Nitril (Id) can be produced by dissolving triflate (Ic) in 1,2-dichloroethane or the like, adding cyanotri n-butyltin and tetrakis (triphenylphosphine) palladium (0) and stirring. The reaction temperature is preferably 10-100 ° C. The amide (Ie) can be obtained by dissolving nitrile (Id) in methanol, tetrahydrofuran, etc. and hydrolyzing with sodium hydroxide. The reaction temperature is preferably 0 to 100 ° C. Amide (Ie) can also be produced by converting nitrile (Id) to a carboxylic acid and then condensing with ammonia water, salt ammonia or the like using an appropriate condensing agent.

 The above-mentioned compounds (Ia to Ie) of the present invention can be converted into other derivatives of the present invention by further modification based on ordinary knowledge of organic chemistry.

[0129] The compound (I), a salt thereof or a solvate thereof of the present invention exhibits a potent antiplatelet action. Even in the high shear stress-induced thrombosis model, thrombus formation was strongly inhibited. Therefore, the compound (1) of the present invention, a salt thereof, or a solvate thereof is used in mammals including humans such as myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris, etc.), ischemic brain. Vascular disorders (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorders, occlusion after artificial blood vessel replacement, coronary artery bypass (CABG), percutaneous transluminal coronary angioplasty (PTCA) ), Stent placement, etc.) It is useful as a preventive and Z or therapeutic agent for ischemic diseases caused by thrombosis / embolism such as thrombotic occlusion after diabetic retinopathy, nephropathy, obstruction at the time of cardiac valve replacement, etc. It is also useful as a prophylactic and Z or therapeutic agent for thromboembolism associated with vascular surgery, extracorporeal blood circulation, and the like. Furthermore, it is useful for improving ischemic symptoms such as ulcer, pain, and cold feeling associated with chronic arterial occlusion.

 When the compound (I) of the present invention, a salt thereof or a solvate thereof is used as a medicine, the dosage varies depending on the age, sex, symptoms, etc. of the patient, but the daily dose per adult is 0.1 mg. ~: Lg is particularly preferred 0.5 mg to 500 mg force S is preferred. In this case, the daily dose can be administered in several divided doses, and if necessary, the daily dose can be administered in excess of the above-mentioned daily dose.

 [0130] A pharmaceutical comprising the compound (I) of the present invention, a salt thereof or a solvate thereof as an active ingredient can be used depending on the administration method and dosage form as necessary, and its preparation is usually used. There are no particular restrictions on the administration method and dosage form, as long as a pharmaceutically acceptable carrier is added as necessary in the preparation method of various preparations and a dosage form that matches the administration method is selected. Yes.

 [0131] Examples of oral preparations include liquid preparations such as liquids, syrups, elixirs, suspensions, and emulsions in addition to solid preparations such as tablets, powders, granules, pills, and capsules. Can be mentioned.

 [0132] As an injection, compound (I), a salt thereof or a solvate thereof may be dissolved and filled in a container, or it may be used as a solid preparation by lyophilization or the like. Good

[0133] When preparing these preparations, pharmaceutically acceptable additives such as binders, disintegrants, dissolution accelerators, lubricants, fillers, excipients and the like are added as necessary. Select and use Togashi.

 Example

 [0134] Next, the present invention will be described in detail with reference to Reference Examples, Examples and Test Examples.

 [Reference Example 1] 5 Hydrazino 2-methoxypyridine hydrochloride

[0135] [Chemical 13]

[0136] 5 A solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise to a concentrated hydrochloric acid (50 ml) solution of 5 amino-2-methoxypyridine (6.21 g) over 60 minutes at the same temperature. Stir for 30 minutes. A solution of tin (II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 ml) was added dropwise to the reaction solution at an internal temperature of about 10 ° C over 30 minutes, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a solution of sodium hydroxide (75 g) in water (300 ml) and jetyl ether were added to the reaction solution to separate the layers. The aqueous layer was extracted twice with Jetyl ether. Further, the aqueous layer was saturated with sodium chloride, extracted with jetyl ether, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, 1M hydrochloric acid ethanol solution (50ml) was added to the filtrate and stirred. The precipitated solid was collected by filtration, washed with jetyl ether and dried to give the title compound (5.02g, 57%) Got.

 'H-NMR (400MHz, DMSO-d) δ: 3.81 (3Η, s), 6.82 (1Η, d, J = 8.8H

 6

 z), 7. 57 (1H, dd, J = 8. 8, 2. 9Hz), 7. 97 (1H, d, J = 2. 9Hz), 8. 55—9.2

0 (1H, br), 10. 13- 10. 50 (3H, br).

 MS (ESI) m / z: 140 (M + H) +.

[0137] [Reference Example 2] 5 Hydrazino 2-methoxypyridine

[0138] [Chemical 14]

5 A solution of amino-2-methoxypyridine (6.207 g) in concentrated hydrochloric acid (50 ml) was added dropwise with ice-cooled sodium nitrite (3.795 g) in water (20 ml) over 80 minutes. Stir for minutes It was. A solution of tin chloride (IV) dihydrate (39.5 g) in concentrated hydrochloric acid (30 ml) was added dropwise to the reaction solution over 60 minutes at an internal temperature of about 10 ° C., followed by stirring at room temperature for 12.5 hours. Under ice-cooling, a solution of sodium hydroxide (54 g) in water (200 ml) and chloroform was added to the reaction solution, and the insoluble material was removed by filtration. Further, the aqueous layer was extracted twice with black mouth form, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give the title compound (4.23 g, 60%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3. 50— 3.68 (2Η, br), 3. 88 (3Η, s), 4.8

 Three

 6- 5. 03 (1H, br), 6. 66 (1H, d, J = 8.8Hz), 7. 20 (1H, dd, J = 8. 8, 2. 9H z), 7. 77 ( 1H, d, J = 2.9Hz).

 MS (ESI) m / z: 140 (M + H) +.

[0140] [Reference Example 3] 1— (6-Methoxy-3 pyridyl) -5- (2 pyridyl) 1H pyrazole

 3—Power Norebonic acid

[0141] [Chemical 15]

[0142] 1) 4— (2 Pyridyl) 2, 4 Dioxobutanoic acid ethyl ester

Under argon atmosphere, 60% sodium hydride (0.991g) in N, N-dimethylformamide (30ml) suspension at 0 ° C was added dropwise with 2acetylylidine (1.39ml) and stirred for 5 minutes at room temperature. Stir for 30 minutes. To the reaction solution, jetyl oxalate (3.36 ml) was added dropwise at 0 ° C., and the mixture was stirred for 10 minutes and then at room temperature for 18 hours. Water and jetyl ether were added to the reaction solution and the phases were separated. The aqueous layer was neutralized with a 1N aqueous hydrochloric acid solution (24.8 ml), and separated by adding ethyl acetate. The organic layer was washed twice with water and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol monochloroform). 4 1 (2 Pyridyl) 2, 4 Dioxobutanoic acid ethyl ester (1.12 g, 41%) Was obtained as a solid. NMR-NMR (400MHz, CDC1) δ: 1.40—1.43 (3H, m), 4.38—4.43 (2H,

 Three

 m), 7.51-7.54 (1H, m), 7.62 (1H, s), 7.89— 7.93 (1H, m), 8.18 (1H, d, J = 8.0Hz), 8.73 (1H, d, J = 4.4Hz ).

MS (El) m / z: 221 (M ⁺ ).

[0143] 2) 5 Hydroxy 1- (6-Methoxy-1-pyridyl) 5- (2 Pyridyl) 4, 5 Dihydro 1H Pyrazole 3 Carboxylic acid ethyl ester

 A solution of the above 4- (2 pyridyl) 2,4 dioxobutanoic acid ethyl ester (1.10 g) and 5-hydrazino-1-methoxypyridine (0.692 g) of Reference Example 2 in ethanol (22 ml) was heated to reflux for 14 hours. After air-cooling, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane ethyl acetate) and then purified again by silica gel column chromatography (tonolene acetone). 5 Hydroxy 16-methoxy 3 Pyridyl) -5- (2 pyridyl) -4,5 dihydro-1 1H pyrazole-1-3-carboxylic acid ethyl ester (0.575 g, 34%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.37—1.40 (3Η, m), 3.47—3.64 (2Η,

 Three

 m), 3.81 (3H, s), 4.35—4.40 (2H, m), 6.57— 6.59 (1H, m), 6.85 (1H, m), 7.34-7.38 (1H, m), 7.45— 7.48 (1H, m), 7.52-7.59 (2H, m), 7.79-7.83 (1H, m), 8.55-8.57 (1H, m).

[0144] 3) 1— (6-Methoxy-1-pyridyl) -5- (2 Pyridyl) 1H Pyrazole 3-Strength Rubonic acid ethyl ester

 To the above solution of 5-hydroxy-1- (6-methoxy-1-pyridyl) -5- (2 pyridinole) -4,5-dihydro-1H pyrazole-3-carboxylic acid ethyl ester (0.546 g) in ethanol (11 ml), acetic acid (0.456 ml) was heated to reflux for 4 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate were added to the reaction solution for separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexyl monoacetate). 1- (6-Methoxy-1-pyridyl) -5- (2-pyridyl) —1H Pyrazole-3-ethyl carboxylic ester (0.516 g, quantitative) was obtained as a solid.

'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.2Hz), 3.95 (3H, s), 4 .46 (2H, q, J = 7.2Hz), 6.76— 6.78 (1H, m), 7.22— 7.28 (2H, m), 7.3 5-7.37 (1H, m), 7.66— 7.71 (2H, m), 8.11 (1H, m), 8.52-8.54 (1H, m).

 MS (FAB) m / z: 325 (M + H) +.

[0145] 4) Title compound

 1- (6-Methoxy-1-pyridyl) -5- (2-pyridyl) 1H Pyrazole-3 Into a methanol (8.8 ml) solution of ethylsterol rubonic acid (0.438 g) at room temperature, 1N aqueous sodium hydroxide solution (3.38 ml) ) Was added and stirred for 4 hours. The reaction solvent was evaporated under reduced pressure, 1N aqueous hydrochloric acid solution (3.38 ml) was added to the resulting residue for neutralization, water and ethyl acetate were added to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (0.344 g, 86%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.89 (3Η, s), 6.89 (1Η, d, J = 8.8H

 6

 z), 7.33-7.37 (2H, m), 7.67— 7.73 (2H, m), 7.85— 7.89 (1H, m), 8

14 (1H, d, J = 2.4Hz), 8.44— 8.46 (1H, m), 13.06 (1H, br).

 MS (FAB) m / z: 297 (M + H) +.

[0146] [Reference Example 4] 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) 1H Pyrazo 1-Lu 3-Strong Rubonic Acid

[0147] [Chemical 16]

[0148] Method A)

 1) 1— (6 Black mouth 3 Pyridazil) 5— (2 Pyridyl) -1H-pyrazole 1 3 -carboxylic acid ethyl ester

3 Chloro-6 hydrazinopyridazine (1.59g) and 4 of 1 (2 pyridyl) -2,4-dioxobutanoic acid ethyl ester (2.45g) in Reference Example 3 1) in ethanol (60ml) for 6 hours After heating to reflux, concentrated hydrochloric acid (lml) was added to the reaction mixture, and the mixture was further heated to reflux for 1 hr. After air cooling, the reaction solvent was evaporated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl hexane acetate). 1- (6 Closyl 3 pyridazil) -5- (2 Pyridyl)-1H pyrazole 3-Strong rubonic acid ethyl ester (1.50 g, 41%) was obtained as a solid

'H-NMR (400MHz, CDC1) δ: 1.44 (3Η, t, J = 7. OHz), 4.46 (2H, q, J

 Three

 = 7. OHz), 7.23 (1H, s), 7.24— 7.27 (1H, m), 7.62— 7.65 (1H, m), 7.69 (1H, d, J = 9. OHz), 7.76— 7.81 ( 1H, m), 8.10 (1H, d, J = 9. OHz), 8.40 (1H, d, J = 4.6Hz).

 LC MSm / z: 330 (M + H) +.

[0149] 2) 1— (6-Methoxy-1-pyridazil) 5-— (2 Pyridyl) 1H Pyrazole 1-3 Carbonic acid methyl ester

 Add 1- (6—black 3 pyridazil) -5- (2-pyridyl) -1H pyrazole-3 carboxylic acid ethyl ester (1.50 g) in methanol (45 ml) with 28% sodium methoxide-methanol solution (3 ml). The mixture was heated to reflux for 2 hours. After air cooling, the reaction solution was evaporated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl hexane acetate). 1- (6-Methoxy-3-pyridazil) -5- (2-pyridyl) — 1H Pyrazole-3-carboxylic acid methyl ester (480 mg, 34%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.99 (3Η, s), 4.10 (3Η, s), 7.15 (1H, d

 Three

, J = 9.3Hz), 7.21-7.23 (1H, m), 7.24 (1H, s), 7.58—7.61 (1H, m), 7.73-7.78 (1H, m), 7.93 (1H, d, J = 9.3 Hz), 8.40- 8.41 (1H, m). LC-MSm / z: 312 (M + H) ⁺ .

[0150] 3) Title compound

Above 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) -1H pyrazole -To a solution of carboxylic acid methyl ester (475 mg) in ethanol (10 ml) and tetrahydrofuran (10 ml), 1N aqueous sodium hydroxide solution (3 ml) was added and stirred at room temperature for 20 hours. The reaction solution was neutralized by adding 1N aqueous hydrochloric acid solution (3 ml) under ice-cooling, and the reaction solution was separated by adding a mixed solvent of chloroform-form methanol (10: 1), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (300 mg, 66%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 4.04 (3Η, s), 7.32― 7.35 (1Η, m)

 6

 , 7.41 (1Η, s), 7.49 (1H, d, J = 9.3Hz), 7.80— 7.82 (1H, m), 7.87—7.91 (1H, m), 7.99 (1H, d, J = 9.3Hz ), 8.35-8.36 (1H, m).

 LC MSm / z: 298 (M + H) +.

[0151] Method B)

 1) 4- (2 Pyridyl) -2, 4 Dioxobutanoic acid methyl ester

 Under an argon atmosphere, a solution of dimethyl oxalate (5.00 g) and sodium methoxide (2.29 g) in methanol (26 ml) was added with a solution of 2 acetyl pyridine (2.56 g) in methanol (26 ml) at room temperature and stirred for 15 minutes. The mixture was stirred at 60 ° C for 45 minutes. After air cooling, water was added to the reaction solution and washed with diethyl ether. A saturated aqueous solution of sodium chloride and chloroform was added to the aqueous layer for separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (2 pyridyl) 2,4 dioxobutanoic acid methyl ester (3.44 g, 79%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.94 (3Η, s), 7.54—7.50 (1Η, m), 7.6

 Three

 4 (1H, s), 7.93-7.89 (1H, m), 8.19— 8.16 (1H, m), 8.74— 8.72 (1H, m).

EI-MSm / z: 207 (M ⁺ ).

[0152] 2) 1— (6 Chromium 3 Pyridazil) 5— (2 Pyridyl) 1H Pyrazole 1 3- Carboxylic acid methyl ester

A solution of the above 4- (2-pyridyl) -2,4 dioxobutanoic acid methyl ester (4.143 g) and 3-chlorodiethyl hydrazinopyridazine (2.891 g) in methanol (100 ml) was heated to reflux for 109 hours. Concentrated hydrochloric acid (2 ml) was added to the reaction solution, and the mixture was further heated to reflux for 6 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution, and the mixture is separated. And washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 1— (6 Kuroguchi 1 Pyridazil) 5 — (2 Pyridyl) 1H Pyrazole 1 3 Obtained.

 'H-NMR (400MHz, CDC1) δ: 4.00 (3Η, s), 7.24— 7.28 (1Η, m), 7.2

 Three

 4 (1H, s), 7.64 (1H, dt, J = 7. 8, 1.2 Hz), 7.70 (1H, d, J = 9.0 Hz), 7. 79 (1H, td, J = 7. 8, 1. 7Hz), 8. 09 (1H, d, J = 9.0 Hz), 8. 38— 8. 41 (1H, m)

ESI-MSm / z: 316 (M + H) ⁺ .

 [0153] 3) 1— (6-Methoxy-1-pyridazil) 5-— (2 Pyridyl) 1H Pyrazole 1-3 Carbonic acid methyl ester

 1- (6-Crop 3 Pyridazil) -5- (2-Pyridyl) -1H Pyrazole 3-Carboxylic acid methyl ester (2.98 lg) in methanol (190 ml) (1.530 g) was added and stirred for 19 hours. To the reaction solution was added 1N aqueous hydrochloric acid (19 ml), methanol was distilled off under reduced pressure, water was added to the resulting residue, the insoluble solid was collected by filtration, and dried to give 1- (6-methoxy-1-pyridazil-). 5- (2 Pyridyl) 1H Pyrazolux 3-carboxylic acid methyl ester (2.571 g, 87%) was obtained as a solid.

 [0154] 4) Title compound

 1- (6-Methoxy-3 pyridazyl) -5- (2 pyridyl) -1H pyrazole-3 carboxylic acid methyl ester (2. 20 g) in methanol (30 ml) and tetrahydrofuran (3 Oml) mixed solution at room temperature 1N sodium hydroxide aqueous solution (15 ml) was added and stirred for 2.5 hours. Under ice-cooling, a 1N aqueous hydrochloric acid solution (15 ml) and a mixed solvent of chloroform-methanol (10: 1) were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, isopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration to obtain the title compound (1.42 g, 47.6%).

 [0155] [Reference Example 5] 1— (6-Methoxy-1-pyridyl) -5- (1H-pyrrole-2-yl) pyrazo

[0156] [Chemical 17]

[0157] Sodium ethoxide (1.63 g) in ethanol (20 ml) was stirred with ice-cooled ethyl oxalate (3.1 Oml) and 1— [1 (phenylsulfol) 1 H pyrrole 2 1 Ethanone (2.49 g) was stirred at room temperature for 5 hours. To this reaction solution, 5 hydrazino-2-methoxypyridine hydrochloride (2.52 g) of Reference Example 1 and ethanol (20 ml) were heated under reflux for 14.5 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was separated. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl hexane acetate) 1- (6 methoxy-3-pyridyl) -5- [1- (phenol sulfone). -L)-1H pyrrole-2-yl] Pyrazol-3-strong rubonic acid ethyl ester (3.28 g, 72%) was obtained as an oil. To a solution of this ethyl ester (3.28 g) in ethanol (22 ml) was added 1N aqueous sodium hydroxide solution (22 ml), and the mixture was stirred at room temperature for 2 days. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the resulting solid was collected by filtration to give the title compound (1.40 g, 68%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.94 (3Η, s), 5. 49— 5. 51 (1Η, m)

 6

 , 5. 98-6. 00 (1H, m), 6. 87— 6. 89 (1H, m), 6. 98 (1H, dd, J = 8. 8, 0.5

Hz), 7. 08 (1H, s), 7. 80 (1H, dd, J = 8. 8, 2. 7 Hz), 8. 25 (1H, dd, J = 2.7

, 0.5Hz), 11.39 (1H, br s).

 ESI— MSm / z: 285 (M + H) +.

[0158] [Reference Example 6] 1— (6-Methoxy-1-pyridyl) -5- (2 pyrajur) -1-H

[0159] [Chemical 18]

[0160] 1— (2-Virazyl) 1 1 Etanone (1.22 g) in tetrahydrofuran (10 ml) was cooled to 78 ° C. and cooled with lithium bis (trimethylsilyl) amide (1. OM in tetrahydrofuran, 1 1 Oml) was stirred for 55 minutes, and then cetyl oxalate (2.05 ml) was added, and the mixture was gradually returned to room temperature and stirred for 6 and a half hours. A 1N aqueous hydrochloric acid solution (11 ml), water, and jetyl ether were added to the reaction solution to separate the layers. Further, sodium chloride was added to the aqueous layer and the mixture was saturated and extracted with ethyl acetate. The combined organic layer was evaporated under reduced pressure to give a crude purified product of 1 (2 pyrajur) -2, 4 dioxobutanoic acid ethyl ester (1 83 g, 82%) was obtained as a solid. To a suspension of this crude product (1.58 g) in ethanol (20 ml), a suspension of 5 hydrazinone 2-methoxypyridin hydrochloride (1.50 g) in Reference Example 1 in ethanol (80 ml) was suspended in triethylamine (1.9 ml). ) Was added and the prepared solution was added and heated to reflux for 19 hours. Further, acetic acid (5 ml) was added to the reaction solution, and the mixture was heated to reflux for 1.5 days. After air cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexane acetate) 1- (6-Methoxy-1-pyridyl) -5- (2 pyrazyl) 1H pyrazole 1-Carboxylic acid ethyl ester (1.05 g, 45%) was obtained as a solid. To a solution of the obtained 1H-prazole-3-strong rubonic acid ethyl ester (1.05 g) in ethanol (30 ml), 1N sodium hydroxide aqueous solution (10. Oml) was added and stirred at room temperature for 16 hours. To the reaction solution, 1N aqueous hydrochloric acid (15 ml), water and ethyl acetate were separated, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (0.883 g, 92%) as a solid. The product was subjected to the next reaction without purification.

 [0161] [Reference Example 7] 5 Hydrazin 2 Methinorepyridine

[0162] [Chemical 19]

[0163] 1) (6 Methylpyridine-3-yl) strong rubamic acid tert butyl ester

 6 To a suspension of methylnicotinic acid (21.58 g) in 1,4 dioxane (300 ml) at room temperature, triethylamine (23. Oml), diphenylphosphoryl azide (35.6 ml), and tert-butanol (30 Oml) was added and the mixture was heated to reflux for 18 hours. After cooling with air, the reaction solvent was distilled off under reduced pressure, and the residue obtained was separated by adding chloroform and water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form ethyl acetate) (6-methylpyridin-3-yl) carnomic acid tert butyl ester (28. 7g, 88%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.54 (9Η, s), 2.49 (3Η, s), 6.52 (1H, br

 Three

 ), 7.09 (1H, d, J = 8.6Hz), 7.86 (1H, br), 8.29 (1H, d, J = 2.7Hz). EI MSm / z: 208 (M) +.

[0164] 2) Title compound

 Concentrated hydrochloric acid (100 ml) was gradually added to (6 methylpyridine-3-yl) carnomic acid tert butyl ester (28.7 g) at 0 ° C. and stirred for 30 minutes. While maintaining the internal temperature of the reaction solution at 0-5 ° C., a solution of sodium nitrite (10.5 lg) in water (38 ml) was added over 30 minutes and then stirred for 15 minutes. This reaction solution was added dropwise to a solution of tin chloride (IV) dihydrate (108.7 g) in concentrated hydrochloric acid (54 ml) over 50 minutes while maintaining the internal temperature of the reaction solution at 0-5 ° C. Stir for 1 hour. While maintaining the internal temperature of the reaction solution at 0 to 10 ° C., a 6N sodium hydroxide aqueous solution (700 ml) and a mixed solvent of chloroformic formaldehyde methanol (10: 1) were added to the reaction solution for separation. The insoluble suspension of the organic layer was filtered off through celite, and the filtrate solvent was washed with water. The aqueous layer was extracted with a mixed solvent of formaldehyde methanol (10: 1), the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give the title compound (7.66 g, 45%) as a solid.

'H-NMR (400MHz, DMSO- d) δ: 2. 29 (3Η, s), 3. 97 (2Η, br), 6. 66 ( 1H, br), 6.94 (1H, d, J = 8.3Hz), 7.05 (1H, dd, J = 3.0, 8.3Hz), 7.98 (

1H, d, J = 3.OHz).

 ESI MSm / z: 124 (M + H) +.

[0165] [Reference Example 8] 5- (5-Methyl-2-virazil) -1 (6-Methyl-3-pyridyl) -1H pyrazonole 3-force norebonic acid

[0166] [Chemical 20]

[0167] 1) 5-Methylvirazine 2-Strong rubonic acid N-Methoxy-N-methylamide

 5-methylbilazine mono-2-carboxylic acid (13.0 g), 3- (3 dimethylaminopropyl) mono-1-ethylcarbodiimide hydrochloride (19.8 g), 1-hydroxybenzotriazole (14. Og) and N, To a solution of O dimethylhydroxyamine hydrochloride (10. lg) in N, N dimethylformamide (130 ml) was added triethylamine (28.9 ml) at room temperature and stirred for 63 hours. Water and ethyl acetate were added to the reaction solution for separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane acetate). 5-Methylvirazine 2 carboxylic acid N-methoxy N-methylamide (12.3 g, 72%) Was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.63 (3Η, s), 3.41 (3Η, s), 3.74 (3H, s)

 Three

 , 8. 46 (1H, s), 8. 82 (1H, s).

 FAB MSm / z: 182 (M + H) +.

[0168] 2) 1-(5-methylvirazine 2-yl) 1 Ethanone

Under argon atmosphere, add 5-methylvirazine 2 carboxylic acid N-methoxy-1-N-methylamide (12.2 g) in tetrahydrofuran (183 ml) to a solution of methyllithium (1.02 M in jetyl ether, 72.6 ml under cooling at 78 ° C. ) For 20 minutes and then dripped for 130 minutes. Stir. Water and ethyl acetate were added to the reaction solution at o ° c, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexane acetate) 1- (5-methylvilazine 2-yl) 1-ethanone (7.90 g, 86% ) Was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.66 (3Η, s), 2.70 (3Η, s), 8.50 (1H, m

 Three

 ), 9.11 (1H, d, J = l.5Hz).

ESI-MSm / z: 137 (M + H) ⁺ .

[0169] 3) 4- (5-Methylvirazine-2-yl) -1,4 dioxobutanoic acid ethyl ester Under argon atmosphere, 1 ( ₅ -methylvirazine-2-yl) -1 Ethanone (7.89 g) in tetrahydrofuran ( To the solution, lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 63.7 ml) was added dropwise over 20 minutes with cooling at −78 ° C., followed by stirring for 30 minutes. After dropwise addition of decyl oxalate (11.8 ml) to the reaction solution, the mixture was stirred at 78 ° C for 10 minutes, at 0 ° C for 30 minutes, and further at room temperature for 1.5 hours. Water and jetyl ether are added to the reaction solution, and the mixture is separated. A saturated aqueous solution of ammonium chloride is extracted into the aqueous layer with cake form, and the aqueous layer is further extracted with chloroform. Dry with sodium. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (5-methylbiazine 2yl) 2,4 dixobutanoic acid ethyl ester (4.92 g, 36%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.39—1.43 (3Η, m), 2.69 (3Η, s), 4.3

 Three

 8-4.43 (2H, m), 7.60 (1H, s), 8.55 (1H, m), 9.21 (1H, d, J = l.2Hz)

FAB MSm / z: 237 (M + H) +.

[0170] 4) 5- (5-Methyl-2-pyriduryl) -1- (6-methyl-3-pyridyl) 1H Pyrazole 3-Carboxylic acid ethyl ester

A solution of ethanol (90 ml) in 4- (5-methylvirazine-2-yl) -2,4-dioxobutanoic acid ethyl ester (4.5 lg) and 5-hydrazino 2-methylpyridine (2.35 g) in Reference Example 7 was heated to reflux for 80 minutes. Acetic acid (5.46 ml) was added to the reaction solution, and the mixture was further refluxed for 15 hours. Furthermore, concentrated hydrochloric acid (3 ml) was added to the reaction solution, and the mixture was heated to reflux for 1 hour. After air cooling, saturated sodium bicarbonate and chloroform are added to the reaction mixture, and the mixture is separated. And dried. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone-toluene). 3-Carboxylic acid ethyl ester (1.72 g, 28%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.44 (3Η, t, J = 7.1Hz), 2.58 (3H, s), 2

 Three

 .62 (3H, s), 4.48 (2H, q, J = 7.1Hz), 7.25 (1H, d, J = 8.3Hz), 7.34 (1 H, s), 7.73 (1H, dd, J = 8.3, 2.7Hz), 8.34 (1H, m), 8.40- 8.41 (1H, m), 8.59 (1H, d, J = l.5Hz).

 FAB MSm / z: 324 (M + H) +.

[0171] 5) Title compound

 5- (5-Methyl 2-pyrazuryl) 1- (6-Methyl 3-pyridyl) 1H Pyrazo 1-Lu 3-Strong rubonic acid ethyl ester (1.71 g) in tetrahydrofuran (34 ml) suspension at room temperature with lithium hydroxide A solution of Japanese product (0.244 g) in water (17 ml) was stirred for 100 minutes. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (5.82 ml), and then water (250 ml) was added. The precipitated solid was collected by filtration to give the title compound (1.15 g, 74%) as a solid. 'H-NMR (400MHz, DMSO-d) δ: 2.50— 2.53 (6Η, m), 7.35 (1Η, d, J

 6

 = 8.3Hz), 7.48 (1H, m), 7.72 (1H, dd, J = 8.3, 2.4Hz), 8.39 (1H, m)

, 8.42 (1H, d, J = 2.4Hz), 8.87 (1H, s), 13.14 (1H, br s).

 FAB MSm / z: 296 (M + H) +.

[0172] [Reference Example 9] 5- (5-Methoxy-2-pyridyl) -1 (6-methyl-3-pyridyl) 1H pyrazonole 3-force norebonic acid

[0173] [Chemical 21]

[0174] 1 ) 5—メトキシピリジン 2 カルボン酸 N—メトキシー N メチルアミド アルゴン雰囲気下、水素化ナトリウム（55% in oil, 12. 6g)のジメチルスルホキ シド（100ml)懸濁液に、 0°C冷却下 5 ヒドロキシー2 メチルピリジン（30. Og)のジ メチルスルホキシド（200ml)溶液を 20分間かけて滴下後、 35分間攪拌した。同温で 、反応液にヨウ化メチル（18. 0ml)を 15分かけて滴下し、室温で 2時間攪拌した。反 応液に水とジェチルエーテルを加え分液し、有機層を無水硫酸ナトリウムで乾燥した 。濾別後、減圧下溶媒を留去し、 5—メトキシ— 2—メチルピリジン（18. 7g)を得た。 この粗精製物（18. 7g)のピリジン（187ml)溶液に、二酸化セレン（33. 7g)をカロえ 6 2時間加熱還流した。空冷後、反応液に水とクロ口ホルムを力卩ぇ分液し、有機層を無 水硫酸ナトリウムで乾燥した。濾別後、減圧下溶媒を留去し、 5—メトキシピリジン— 2 —カルボン酸（19. lg)を得た。得られた粗精製物（19. lg)、N, O ジメチルヒドロ キシァミン塩酸塩（16. 3g)、 3—（3 ジメチルァミノプロピル） 1ーェチルーカルボ ジイミド塩酸塩（32. lg)、 1—ヒドロキシベンゾトリアゾール（22. 6g)のジクロロメタン (250ml)懸濁液に、 0°Cでトリェチルァミン (46. 6ml)をカ卩ぇ 30分間攪拌後、室温で 14時間攪拌した。反応液に水とクロ口ホルムを加え分液し、有機層を無水硫酸ナトリ ゥムで乾燥した。濾別後、減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロ マトグラフィー（酢酸ェチル クロ口ホルム）で精製し 5—メトキシピリジン 2 カルボ ン酸 N—メトキシ一 N—メチルアミド（15. 3g, 51%)を油状物として得た。

[0174] 1) 5-Methoxypyridine 2 Carboxylic acid N-Methoxy-M methylamide Under argon atmosphere, sodium hydride (55% in oil, 12.6g) in dimethylsulfoxide (100ml) suspension at 0 ° C Under cooling, a solution of 5 hydroxy-2 methylpyridine (30. Og) in dimethylsulfoxide (200 ml) was added dropwise over 20 minutes, followed by stirring for 35 minutes. At the same temperature, methyl iodide (18.0 ml) was added dropwise to the reaction solution over 15 minutes, and the mixture was stirred at room temperature for 2 hours. Water and jetyl ether were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 5-methoxy-2-methylpyridine (18.7 g). To a solution of this crude product (18.7 g) in pyridine (187 ml), selenium dioxide (33.7 g) was heated and refluxed for 62 hours. After cooling with air, the reaction solution was separated with water and black mouth form, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 5-methoxypyridine-2-carboxylic acid (19. lg). The crude product obtained (19. lg), N, O dimethylhydroxyamine hydrochloride (16.3 g), 3- (3 dimethylaminopropyl) 1-ethyl-carbodiimide hydrochloride (32. lg), 1-hydroxybenzo To a suspension of triazole (22.6 g) in dichloromethane (250 ml) was stirred triethylamine (46.6 ml) at 0 ° C. for 30 minutes and then at room temperature for 14 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate, ethyl acetate). 5-methoxypyridine 2 carboxylic acid N-methoxy 1-N-methylamide (15.3 g) , 51%) as an oil.

 'H-NMR (400MHz, CDC1) δ: 3.44 (3Η, s), 3. 79— 3.84 (3Η, m), 3.9

 Three

 1 (3H, s), 7. 24- 7. 28 (1H, m), 7. 75 (1H, d, J = 8.5 Hz), 8. 30 (1H, d, J = 2.9 Hz).

 FAB MSm / z: 197 (M + H) +.

[0175] 2) 1- (5-Methoxypyridine 2-yl) 1-ethanone

Under an argon atmosphere, ₅ - methoxypyridine - to have use 2-carboxylic acid N- methoxymethyl one N- methylamide (15. 3 g) and (Jefferies chill ether solution of 0. 98M, 87. 5ml) methyllithium and Reference Example 1 (5-Methoxypyridine-2-yl) -1-ethaneone (5.41 g, 46%) was obtained as an oil by the same method as in 8-2).

'H-NMR (400MHz, CDC1) δ: 2.69 (3Η, s), 3.94 (3Η, s), 7.27 (1H, d d, J = 8.5, 2.9Hz), 8.06 (1H, d, J = 8.5Hz), 8.34 (1H, d, J = 2.9Hz) .FAB MSm / z: 152 (M + H) +.

[0176] 3) 4- (5-Methoxy-1-pyridyl) 2,4 dioxobutanoic acid ethyl ester

 In an argon atmosphere, sodium ethoxide (4.86 g) in ethanol (54 ml) was added with ethyl oxalate (9.70 ml) at room temperature, and then the reaction mixture was mixed with 1 (5-methoxypyridine 2-yl) -1 ethanone. A solution of (5.40 g) in ethanol (54 ml) was added dropwise. After stirring at room temperature for 140 minutes, water and jetyl ether were added to the reaction solution, and the mixture was separated. A saturated aqueous ammonium chloride solution was added to the aqueous layer, followed by extraction with black mouth form, and then the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (5-methoxy-2-pyridyl) -2,4 dioxobutanoic acid ethyl ester (5.10 g, 57%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.39—1.43 (3Η, m), 3.96 (3Η, s), 4.3

 Three

 7-4.42 (2H, m), 7.31 (1H, dd, J = 8.8, 2.9Hz), 7.60 (1H, s), 8.16 (1 H, d, J = 8.8Hz), 8.38 (1H, d, J = 2.9Hz).

EI-MSm / z: 251 (M ⁺ ).

[0177] 4) 5- (5-Methoxy-2-pyridyl) 1- (6-Methyl-3-pyridyl) 1H Pyrazole 3-Carboxylic acid ethyl ester

 4- (5-Methoxy-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (4.79 g) and 5-hydrazino-1-methylpyridine (2.35 g) in Reference Example 7 in ethanol (96 ml) were heated under reflux for 1 hour. Acetic acid (5.47 ml) was added to the reaction mixture, and the mixture was further heated to reflux for 63 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone-toluene). 5- (5-Methoxy-1-pyridyl) -1- (6-methyl-3-pyridyl) —1H Pyrazole-3-carboxylic acid ethyl ester (1.49 g, 23%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41—1.44 (3Η, m), 2.59 (3Η, s), 3.8

 Three

 6 (3H, s), 4.43-4.48 (2H, m), 7.16— 7.34 (4H, m), 7.71— 7.73 (1H, m), 8.19 (1H, d, J = 2.8Hz), 8.38 ( (1H, d, J = 2.4Hz).

FAB— MSm / z: 339 (M + H) +. [0178] 5) Title compound

 5- (5-Methoxy-2-pyridyl) 1- (6-Methyl-3-pyridyl) 1H Pyrazolu 3-saponified rubonic acid ethyl ester (1.48 g), the same method as 4) of Reference Example 4 Method B) Gave the title compound (0.970 g, 71%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.53 (3Η, s), 3.84 (3Η, m), 7.23 (

 6

 1H, m), 7.34 (1H, d, J = 8.5Hz), 7.45— 7.48 (1H, m), 7.63— 7.67 (2 H, m), 8.16 (1H, d, J = 3.2Hz), 8.37 ( 1H, d, J = 2.7Hz), 13.03 (1H, br s).

 FAB— MSm / z: 311 (M + H) +.

[0179] [Reference Example 10] 1— (6-Methoxy-3 pyridazil) -5— (1H—Pyroleuro 2 yl)

 -1H-pyrazole 3 carboxylic acid

[0180] [Chemical 22]

[0181] — Under cooling at 78 ° C, 1— [1— (Foulsulfol) — 1H Pyrrole — 2—yl ”1

— Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 11. Oml) was stirred in a tetrahydrofuran (10 ml) solution of ethanone (2.49 g) for 35 minutes. Furthermore, dimethyl oxalate (1.77 g) was added to the reaction solution and stirred for 10 minutes. The temperature was gradually returned to room temperature and stirred for 3.5 hours. Jetyl ether and water were vigorously separated into the reaction solution, and Jetyl ether, 1N hydrochloric acid aqueous solution (11 ml) and ethyl acetate were vigorously separated into the aqueous layer. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. 4- [1— (Phenolsulfol) — 1H-pyrrole-2-yl] -2, 4 Dioxobutanoic acid methyl ester crude product (2.88 g, 85 %) Was obtained as a solid. To this suspension of butanoic acid methyl ester (2.70 g) in methanol (40 ml) was added 3 × 6 hydrazinopyridazine (1.16 g), and the mixture was heated to reflux for 16.5 hours. Add concentrated hydrochloric acid (0.200 ml) and methanol (40 ml) to the reaction mixture. The mixture was heated to reflux. Thereafter, concentrated hydrochloric acid (0.200 ml) was heated under reflux for 2 hours, further concentrated hydrochloric acid (0.200 ml) was added and heated under reflux for 40 minutes. After air cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexane-acetate). 1 (6 Chloro-3-pyridazil) -5- [1 (Phenolsulfonyl) -1H pyrrole-2-yl] 1H pyrazole-3-carboxylic acid methyl ester (2.57 g, 71%) was obtained as an amorphous substance. This pyrazole compound (2.34 g) was dissolved in methanol (50 ml) and tetrahydrofuran (50 ml), sodium methoxide (0.854 g) was added at room temperature, and the mixture was stirred for 7 and a half hours. Further, 1N aqueous sodium hydroxide solution (11. Oml) was added to the reaction solution, and the mixture was stirred for 23 hours. Jetyl ether and water were added to the reaction solution and the phases were separated. The aqueous layer was acidified with 1N aqueous hydrochloric acid and extracted with jetyl ether, and the aqueous layer was extracted with ethyl acetate. Further, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. Methanol and jetyl ether were added to the resulting residue, the resulting solid was filtered off, and the filtrate solvent was evaporated under reduced pressure to give the title compound (0.984 g, 65% ) Was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 4.12 (3Η, s), 5. 67— 5. 69 (1Η, m)

 6

 , 6. 00-6. 02 (1Η, m), 6. 89— 6. 91 (1Η, m), 7. 11 (1Η, s), 7. 53 (1Η, d

, J = 9.3Hz), 7.92 (1Η, d, J = 9.3Hz), 11.40 (1Η, br s).

 ESI— MSm / z: 286 (Μ + Η) +.

[0182] [Reference Example 11] 1 (6-Methoxy-3-pyridyl)-5- (1H-Pyro 1-L) -1

Η-Pyrazole 3-carboxylic acid

[0183] [Chemical 23]

[0184] 1) 1— (6-Methoxy-1-pyridyl)-5- (1H-pyrrole 1-yl) 3-carboxylic acid ethyl ester

 To a suspension of sodium ethoxide (3.40 g) in tert-butyl methyl ether (30 ml) was slowly charged with cetyl oxalate (6.79 ml) at room temperature, and the mixture was stirred at 60 ° C. for 10 minutes. Acetonitrile (2.61 ml) was slowly heated to reflux for 4 hours. After cooling with air, the resulting solid was collected by filtration to give 1-ciano 3 ethoxy 1-3-oxo 1-propene 1-ol sodium salt (6.17 g, 75%) as a solid. In Reference Example 2, a solution of 5 hydrazino-2-methoxypyridin (5. OOg) in ethanol (100 ml), 1M hydrochloric acid in 1 ethanol (36. Oml) and the above 1-cyano-3-ethoxy-3-oxo-1-propene-2 —Allnatrium salt (5.86 g) was added and heated to reflux for 16 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane). 5-Amino 1- (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid Ethyl ester (5.09 g, 54%) was obtained as a solid. 2,5-Dimethoxytetrahydrofuran (1.94 ml) was added to an acetic acid (50 ml) solution of the 5-aminovirazole compound (2.62 g), and the mixture was heated to reflux for 3 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexane acetate) 1- (6-methoxy-1-pyridyl) -5- (1H pyrrole 1- 1H) 1H Pyrazole 1-strength rubonic acid ethyl ester (2.92 g, 93%) was obtained as a solid.

'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.1 Hz), 3.94 (3H, s), 4

 Three

 46 (2H, q, J = 7.2 Hz), 6. 28— 6. 30 (2H, m), 6. 64— 6. 65 (2H, m), 6. 7 2 (1H, d, J = 9.3Hz), 6.92 (1H, s), 7.42 (1H, dd, J = 8. 8, 2. 7Hz), 8.00 (1H, d, J = 2.4Hz).

ESI-MSm / z: 313 (M + H) ⁺ .

2) Title compound

1- (6-Methoxy-1-pyridyl) -5- (1H pyrrole 1-yl) 1H Pyrazolu 3 Ethanol (30 ml) of carboxylic acid ethyl ester (2.91 g) and tetrahydrofuran IN aqueous solution of sodium hydroxide (15. Oml) was stirred at room temperature for 3 hours. The reaction solution was acidified with 1N aqueous hydrochloric acid solution, ethyl acetate was added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (2.96 g, quantitative) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3. 87 (3Η, s), 6. 21— 6. 22 (2Η, m)

 6

 , 6. 88-6. 90 (3Η, m), 7. 02 (1Η, s), 7. 61 (1Η, dd, J = 8. 9, 2. 8Hz), 8.

00 (1H, d, J = 2.7Hz).

 ESI— MSm / z: 285 (M + H) +.

[0186] [Reference Example 12] 1— (6-Methoxy-3-pyridazil) -5- (2 pyrajurol) 1H pyrazonole 3-force norebonic acid

[0187] [Chemical 24]

[0188] 1) 1— (6—Black 1 3 Pyridazil) 5 — (2-Pyrazol) 1 1H Pyrazole 1 3 Carboxylic acid methyl ester

— Under cooling at 78 ° C, lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 55. Oml) was added to a solution of 1- (2 pyraduryl) -1-ethanone (6.10 g) in tetrahydrofuran (50 ml). 45 Stir for 45 minutes. To the reaction solution, dimethyl oxalate (8.85 g) was stirred for 10 minutes, and then stirred for 2.5 hours while gradually returning to room temperature. Jetyl ether and water were added to the reaction solution and the phases were separated. A 1N aqueous hydrochloric acid solution (55 ml) was added to the aqueous layer, and the mixture was further saturated with sodium chloride and extracted with diethyl ether. Further, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (2-pyrazur) -2,4-dioxobutanoic acid methyl ester (10.0 g, 96%) as a solid. To a suspension of this crude product of butanoic acid methyl ester (6.27 g) in methanol (150 ml), 3-chloro 6-hydrazinopyridazine (4.35 g) was added and heated to reflux for 18.5 hours. In addition, anti Concentrated hydrochloric acid (0.750 ml) was added to the reaction solution and heated to reflux for 2 hours. After air cooling, the reaction solution was separated by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, methanol was added to the resulting residue, and the resulting solid was collected by filtration. 1— (6 Kuroguchiichi 3 Pyridazil) 5— (2 Pyradur) 1H Pyrazolu 3— Strong rubonic acid methyl ester (5.74 g, 60%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 4.02 (3Η, s), 7.33 (1Η, s), 7.72 (1Η, d

 Three

 , J = 9.3Hz), 8.16 (1Η, d, J = 9. ΟΗζ), 8.42 (1Η, dd, J = 2.4, 1.5Hz), 8.57 (1Η, d, J = 2.7Hz), 8.90 ( 1Η, d, J = l.5Hz).

ESI-MSm / z: 317 [(M + H) ⁺ , ³⁵ C1], 319 [(M + H) +, ^3? C1].

[0189] 2) Title compound

 1— (6—Black mouth 3 Pyridazil) 5 — (2-Pyrazur) 1 1H Pyrazole-3 —Carboxylic acid methyl ester (6.25 g) in methanol (50 ml) and tetrahydrofuran (100 ml) suspension at room temperature Sodium methoxide (1.60 g) was stirred for 8 hours. Further, 1N sodium hydroxide aqueous solution (40. Oml) was stirred in the reaction solution for 19 hours. Diethyl ether and water were separated into the reaction solution and separated, and the aqueous layer was acidified with hydrochloric acid and extracted with jetyl ether. Further, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, methanol and jetyl ether were added to the resulting residue, and the resulting solid was collected by filtration to give the title compound (4.37 g, 74%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 4.04 (3Η, s), 7.51 (1Η, d, J = 9.3H

 6

 z), 7.55 (1H, s), 8.06 (1H, d, J = 9.3Hz), 8.49 (1H, dd, J = 2.4, 1.5Hz

), 8.62 (1H, d, J = 2.4Hz), 9.07 (1H, d, J = l.5Hz).

 ESI— MSm / z: 299 (M + H) +.

[0190] [Reference Example 13] 1— (6-Methoxy-3 pyridyl) -5- (1H pyrazol-3-yl)

1H-pyrazole 3 carboxylic acid

[0191] [Chemical 25]

[0192] 1) 1 {1 [(4 Methylphenol) sulfol] 1H Pyrazole-3-yl} 1 Ethanone

1- (1H Pyrazol-5-yl) 1-Ethanone hydrochloride (2.93 g) in pyridine (60 ml) solution with 4 methylbenzenesulfuryl chloride (5.72 g) 3.5 hours with heating to reflux did. After air cooling, the reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting residue for separation. The organic layer was washed with 1N aqueous hydrochloric acid solution and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was solidified from methanol, jetyl ether and hexane. 1— {1— [(4-Methylphenol) sulfol] 1H Pyrazole-3— 1} -ethanone. _{89 g} , 35%). Furthermore, the residue obtained by distilling off the mother liquor under reduced pressure was solidified from methanol, jetyl ether and hexane. 1 {1 [(4 Methylphenol) sulfol] 1H Pyrazole-3-ylethanone (2. 09 g, 39%) was obtained.

 'H-NMR (400MHz, CDC1) δ: 2.45 (3Η, s), 2.57 (3Η, s), 6.83 (1H, d

 Three

 , J = 2.7Hz), 7.36- 7.38 (2H, m), 7.92— 7.96 (2H, m), 8.10 (1H, d, J = 2.9Hz).

 ESI— MSm / z: 265 (M + H) +.

[0193] 2) 1— (6-Methoxy-1-pyridyl) 5— {1— [(4-Methylphenol) sulfol] 1H Pyrazole-3-yl} 1H Pyrazole-3-Strong rubonate ethyl ester 78 ° C Under cooling, 1 {1 [(4 methylphenol) sulfol] 1H pyrazole-3-yl} — 1-ethanone (3.97 g) in tetrahydrofuran (15 ml) suspension in lithium bis (trimethylsilyl) amide ( 1.0 M tetrahydrofuran solution, 16.5 ml) was stirred for 35 minutes. Add decyl oxalate (3.05 ml) to the reaction mixture and stir for 15 minutes. The mixture was stirred for 3.5 hours while returning. Jetyl ether and water were added to the reaction solution and the phases were separated. The aqueous layer was made acidic with 1N aqueous hydrochloric acid and extracted with jetyl ether. Further, the aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, the resulting solid was filtered off, and the mother liquor was evaporated under reduced pressure. 4 {1 [(4 methylphenol) sulfol] 1H Pyrazole-3-yl} -2,4-dioxobutanoic acid ethyl ester (5.08 g, 92%) was obtained as an oil. A solution of this butyric acid ethyl ester (5.08 g) and 5 hydrazinone 2-methoxypyridine (1.93 g) of Reference Example 2 in ethanol (70 ml) was heated to reflux for 14.5 hours. After air cooling, the reaction mixture was separated by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate). 1- (6-Methoxy-1-pyridyl) 5-- {1- [(4 methylphenol- L) sulfol] 1 H pyrazole 3 yl} — 1H pyrazole-3-carboxylic acid ethyl ester (2.58 g, 39%) was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 1.41 (3Η, t, J = 7.1Hz), 2.45 (3H, s), 4

 Three

 .01 (3H, s), 4.44 (2H, q, J = 7.1Hz), 6.24 (1H, d, J = 2.7Hz), 6.73 (1 H, d, J = 8.8Hz), 7.23 (1H, s ), 7.31 (2H, d, J = 8.5Hz), 7.58 (1H, dd, J = 8.8, 2.7Hz), 7.76 (2H, d, J = 8.3Hz), 8.04 (1H, d, J = 2.7Hz) ), 8. 15 (1H, d, J = 2.7Hz).

ESI-MSm / z: 468 (M + H) ⁺ .

3) Title compound

 1-(6 Methoxy-1-pyridyl) 5— {1— [(4 Methylphenol) sulfol]-1 H -pyrazole 3 yl} Using 1 H pyrazole 3 carboxylic acid ethyl ester (2.58 g) The title compound (1.33 g, 84%) was obtained as a solid in the same manner as in Reference Example 11 2).

 'H-NMR (400MHz, DMSO-d) δ: 3.92 (3Η, s), 6.29 (1Η, br s), 6.9

 6

4 (1Η, d, J = 8.8Hz), 7.14 (1H, s), 7.75 (1H, d, J = 2.2Hz), 7.80 (1H, dd, J = 8.8, 2.7Hz), 8.24-8.25 (1H , m), 13.09 (1H, br s). ESI— MSm / z: 286 (M + H) +.

[0195] [Reference Example 14] 1— (6-Methyl-3-pyridyl) -5- (1-Methyl-1H—Pyroluene 3 yl) 1H Pyrazole-3—Strong rubonic acid

[0196] [Chemical 26]

[0197] 1) 4— (1-Methyl 1H pyrrole 1-yl) 2, 4 Dioxobutanoic acid methyl ester

 3 Using acetyl-1-methyl-1H pyrrole (5.03 g), lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 45 ml) and dimethyl oxalate (9.53 g) In the same manner, 41- (1-methyl-1H-pyrrole-3yl) -2,4-dioxobutanoic acid methyl ester (6.52 g, 76%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.72 (3Η, s), 3.91 (3Η, s), 6. 60— 6. 66

 Three

 (2H, m), 6.70 (1H, s), 7. 37 (1H, s like).

 FAB MSm / z: 210 (M + H) +.

[0198] 2) 1- (6-Methyl-3-pyridyl) -5- (1-methyl 1H pyrrole-3-yl) 1 H pyrazole 3-carboxylic acid methyl ester

4- (1-Methyl-1H pyrrole-3-yl) -2,4 Methyl ester of dioxobutanoic acid (3.00 g) and 5 hydrazino 2-methylpyridine (2.00 g) of Reference Example 7 were added in methanol (80 ml). Heated to reflux for 20 minutes. After air cooling, acetic acid (3.3 ml) was added to the reaction mixture, and the mixture was heated to reflux for 14 hours. After cooling with air, the reaction solvent was distilled off under reduced pressure, and the residue was added with Kuroguchi Form and saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone monochloroform). 1- (6-Methyl 3-pyridyl)-5- (1-methyl 1 H pyrrole 3yl) 1H pyrazole 3 carboxylic acid methyl ester ( 2.96 g, 70%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.62 (3H, s), 3.58 (3H, s), 3.94 (3H, s)

 Three

 , 5.85-5.92 (1H, m), 6.41— 6.46 (1H, m), 6.48— 6.53 (1H, m), 6.9 1 (1H, s like), 7.23 (1H, d, J = 8.1Hz), 7.66 — 7.74 (1H, m), 8.53— 8.60 (1H, m).

 FAB MSm / z: 297 (M + H) +.

[0199] 3) Title compound

 1- (6-methyl-3-pyridyl) -5- (1-methyl-1H pyrrole-3-yl) -1H pyrazole-3-carboxylic acid methyl ester (2.96g) in methanol (25ml) and water (15ml) Lithium hydroxide monohydrate (0.475 g) was added to the suspended solution at room temperature and stirred for 1.5 hours. The reaction solvent was evaporated under reduced pressure, and the resulting residue was neutralized with 1N aqueous hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (1.32 g, 47%).

 'H-NMR (400MHz, DMSO-d) δ: 2.56 (3Η, s), 3.55 (3Η, s), 5.72—

 6

 5.76 (1H, m), 6.65— 6.76 (2H, m), 6.87— 6.90 (1H, m), 7.37— 7.44

(1H, m), 7.76-7.81 (1H, m), 8.44-8.50 (1H, m).

 ESI— MSm / z: 283 (M + H) +.

[0200] [Reference Example 15] 1— (6-Methyl-3 pyridazil) -5— (5-Methyl-2-pyridyl)

1H-pyrazole 3 carboxylic acid

[0201] [Chemical 27]

1) 3-hydrazino 6 methylpyridazine

3 To a suspension of ethanol (45 ml) in 6-methylpyridine (3.00 g) was added hydrazine monohydrate (45 ml) and heated to reflux for 2.5 hours. After air-cooling, the reaction solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (chloroform methanol-water (7 vs. 3 Purification by the lower layer mixed solvent of 1) gave 3 hydrazino-6-methylpyridazine (2.35 g, 81%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.39 (3Η, s), 4.20 (2Η, br), 6.94 (

 6

 1H, d, J = 9.3Hz), 7.18 (1H, d, J = 9.3Hz), 7.64 (1H, br).

ESI-MSm / z: 125 (M + H) ⁺ .

[0203] 2) 1- (5-Methinore 2 Pyridinole)-1 Ethanone

 2 To a solution of bromo-5 picoline (5. Og) in jetyl ether (100 ml), n-butyllithium (1.58M hexane solution, 24 ml) was added dropwise over 5 minutes under cooling at -78 ° C, followed by stirring for 5 minutes. N, N dimethylacetamide (3.5 ml) was added dropwise to the reaction solution, and the mixture was stirred for 2 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to give 1 5-methyl-2-pyridyl) 1 ethanone (3.4 3 g, 87%) as an oil. It was.

 'H-NMR (400MHz, CDC1) δ: 2.42 (3Η, s), 2.71 (3Η, s), 7.62 (1H, d

 Three

 d, J = l.59, 7.93Hz), 7.94 (1H, d, J = 7.93Hz), 8.54 (1H, s).

[0204] 3) 4- (5-Methyl-2-pyridyl) 2, 4 Dioxobutanoic acid ethyl ester

 To a solution of sodium ethoxide (3.5 g) in ethanol (60 ml) was added dropwise ethyl oxalate (7 ml) at room temperature, and then the reaction mixture was mixed with 1- (5-methyl-2-pyridyl) 1-ethanone (3.43 g) in ethanol (40 ml). ) The solution was added and stirred for 2 hours. Water and jetyl ether were added to the reaction solution and separated. The aqueous layer was made caloric and acidic with a 1N hydrochloric acid solution, and then the black mouth form was calorie-separated and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (5-methyl-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (6.8 g) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.40 (3Η, t, J = 7.08Hz), 2.47 (3H, s),

 Three

 4.39 (2H, q, J = 7.08Hz), 7.49 (1H, br), 7.74 (1H, dd, J = l.47, 8.06 Hz), 8.08 (1H, d, J = 8.06Hz), 8.58 (1H , d, J = 0.73Hz).

 EI— MSm / z: 236 (M + H) +.

[0205] 4) 1— (6-Methyl-3 pyridazil) -5- (5-Methyl-2-pyridyl) 1H Villa Zole 3-carboxylic acid ethyl ester

 Acetic acid (4.31 ml) was added to a solution of 4- (5-methyl-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (3.54 g) and 3 hydrazino 6-methylpyridazine (1.87 g) in ethanol (71 ml) at room temperature. Heated to reflux for 15 hours. Further, concentrated hydrochloric acid (4.7 ml) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. After air cooling, saturated sodium hydrogen carbonate and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form ethyl acetate). 1 (6-Methyl-3 pyridazil) -5- (5-Methyl-2 Pyridyl) 1H-pyrazole-3-strong rubonic acid ethyl ester (1.13 g, 23%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41— 1.44 (3Η, m), 2.32 (3Η, s), 2.7

 Three

 2 (3H, s), 4.43-4.48 (2H, m), 7.18 (1H, s), 7.46— 7.56 (3H, m), 7.98 (1H, d, J = 8.8Hz), 8.21 ( 1H, m).

 EI— MSmZz: 323 (M +).

[0206] 5) Title compound

 1- (6-Methyl 3-pyridazil) 5- (5-Methyl 2-pyridyl) 1H-virazol-3- similar to rubonic acid ethyl ester (1.12g) as in 4) of Reference Example 4, Method B) To give the title compound (0.759 g, 74%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.27 (3Η, s), 2.67 (3Η, s), 7.32 (1

 6

 H, s), 7.64-7.69 (2H, m), 7.81 (1H, d, J = 8.8Hz), 7.94 (1H, d, J = 8

.8Hz), 8.15-8.16 (1H, m), 13.16 (1H, s).

 EI— MSmZz: 295 (M +).

[0207] [Reference Example 16] 1— (6-Methoxy-1-pyridyl) 5 -— (4-Pyrimidyl) -1-H pyrazo One-ru 3-Strong rubonic acid

[0208] [Chemical 28]

[0209] 1) 4 Acetyl 2-methylthiopyrimidine

 A mixture of 3,3 dimethylbutan-2-one (25.15 g) and N, N-dimethylformamide dimethyl acetal (126 ml) was heated and stirred at an external temperature of 100 ° C. for 48 hours. After air cooling, the low-boiling components produced in the reaction were distilled off under reduced pressure. Methanol (400 ml), phenol (28.92 g) and sodium methoxide (15.39 g) were added to the resulting residue, and the mixture was heated to reflux for 118 hours. did. After air cooling, sodium methoxide (10.26 g) was added to the reaction solution, and methyl iodide (17.8 ml) was added dropwise over 5 minutes under ice cooling, followed by stirring at room temperature for 5 hours. The reaction solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the resulting residue for separation. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, 3N aqueous hydrochloric acid solution (400 ml) was added to the resulting residue, and the mixture was stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane acetate) to obtain 4-acetyl 2-methylthiopyrimidine (26. 34 g, 82%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.63 (3Η, s), 2.70 (3Η, s), 7.51 (1H, d

 Three

 , J = 4.9 Hz), 8.74 (1H, d, J = 4.9 Hz).

ESI-MSm / z: 169 (M + H) ⁺ .

[0210] 2) 4- (2-Methylthio-4-pyrimidyl) -2,4 dioxobutanoic acid methyl ester Under argon atmosphere, 4-acetyl-2-methylthiopyrimidine (197 mg), lithium bis (trimethylsilyl) amide (1.OM in tetrahydrofuran) 4- (2-methylthio-4-pyrimidyl) 2,4 dioxobutanoic acid methyl ester (294 mg) in the same manner as in Reference Example 8 3) using solution, 1.40 ml) and dimethyl oxalate (276 mg) , 98%) as a solid.

ESI— MSm / z: 255 (M + H) +. [0211] 3) 1— (6-Methoxy-1-pyridyl) -5- (2-methylthio-4-pyrimidyl) -1-H pyrazole 3-carboxylic acid methyl ester

 Using 4- (2-methylthio-4-pyrimidyl) -2,4 dioxobutanoic acid methyl ester (294 mg) and 5 hydrazino 2-methoxypyridine (16 lmg) of Reference Example 2, the same as Reference Example 14 2) The method gave 1- (6-methoxy-3-pyridyl) -5- (2-methylthio-4-pyrimidyl) -1H pyrazole-3-carboxylic acid methyl ester (204 mg, 49%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.14 (3Η, s), 3.98 (3Η, s), 3.99 (3H, s)

 Three

 , 6.83 (1H, d, J = 8.8Hz), 7.03 (1H, d, J = 5.1Hz), 7.45 (1H, s), 7.63 (1H, dd, J = 8.8, 2.7Hz), 8.16 ( 1H, d, J = 2.7Hz), 8.52 (1H, d, J = 5.1 Hz).

 ESI— MSm / z: 358 (M + H) +.

[0212] 4) 1— (6-Methoxy-1-pyridyl) -5- (4-pyrimidyl) -1-H pyrazole-1-3 carboxylic acid methyl ester

 1— (6-Methoxy-1-pyridyl) -5- (2-methylthio-4-pyrimidyl) -1-H-pyrazole-3-carboxylic acid methyl ester (198 mg) in methanol (25 ml) with Raney nickel (excess, active After washing with water and methanol, the mixture was stirred for 16 hours at 120 ° C in the sealed tube. After cooling with air, insoluble material was filtered off from the reaction mixture, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-chloroform) 1 (6 —Methoxy-3pyridyl) -5- (4-pyrimidinyl) -1H-pyrazole 3 carboxylic acid methyl ester (123 mg, 71%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.98 (3Η, s), 3.99 (3Η, s), 6.82 (1H, d

 Three

 , J = 8.8Hz), 7.34 (1H, d, J = 5.1Hz), 7.48 (1H, s), 7.67 (1H, dd, J = 8.8, 2.7Hz), 8. 14 (1H, d, J = 2.7Hz), 8.75 (1H, d, J = 5.1Hz), 9.11 (1 H, s).

ESI-MSm / z: 312 (M + H) ⁺ .

[0213] 5) Title compound 1- (6-Methoxy-1-pyridyl) -5- (4-pyrimidyl) -1- 1H Pyrazole-1-3-Method similar to 4) of Reference Example 4 Method B) using 3-carboxylic acid methyl ester (122 mg) Gave the title compound (lOOmg, 86%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 4.00 (3Η, s), 6.84 (1Η, d, J = 8.8Hz), 7

 Three

 .37 (1H, dd, J = 5.4, 1.2Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 8.8, 2.7 Hz), 8.16 (1H, d, J = 2.7Hz), 8.78 ( 1H, d, J = 5.4Hz), 9.12 (1H, d, J = 1.2Hz).

 ESI— MSm / z: 298 (M + H) +.

[0214] [Reference Example 17] 4-Methoxypiperidine trifluoroacetate

[0215] [Chemical 29]

[0216] 1) 4-Methoxypiperidine 1 Powerful rubonic acid tert butyl ester

 Under an argon atmosphere, a suspension of sodium hydride (60%, 0.477 g) in N, N-dimethylformamide (20 ml) at room temperature with 4-hydroxypiperidine 1 carboxylic acid tert-butyl ester (2.00 g) N, N Dimethylformamide (20 ml) solution was added dropwise and stirred for 15 minutes. Methyl iodide (0.742 ml) was added dropwise to the reaction solution and stirred for 2 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane). 4 Methoxypiperidine 1 Carboxylic acid tert-butyl ester (1.43 g, 67%) was oily. Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 1.39—1.54 (2Η, m), 1.46 (9Η, s), 1.8

 Three

 1-1.84 (2H, m), 3.05— 3.12 (2H, m), 3.31— 3.39 (1H, m), 3.35 (3H, s), 3.74-3.77 (2H, m).

[0217] 2) Title compound

To a solution of 4-methoxypiperidine 1 carboxylic acid tert butyl ester (1.42 g) in dichloromethane (28 ml), trifluoroacetic acid (14 ml) was stirred at room temperature for 2.5 hours. . The solvent of the reaction mixture was evaporated under reduced pressure to give the title compound (2.65 g, quantitative) as an oil. 'H-NMR (400MHz, CDC1) δ: 1. 98— 2. 02 (4Η, m), 3. 19— 3. 23 (2Η,

 Three

 m), 3.30- 3. 42 (2H, m), 3.37 (3H, s), 3.54-3.60 (1H, m).

[0218] [Reference Example 18] 4, 4 Difluoropiperidine hydrochloride

[0219] [Chemical 30]

[0220] 1) 1 Benzyl 1, 4, 4 Difluoropiperidine

 In an argon atmosphere, 1-benzyl-4 piperidone (5.00 g) in benzene (200 ml) was added dropwise with dethylaminosulfur trifluoride (8. 38 ml) at 0 ° C and stirred for 30 minutes, then heated for 18 hours. Refluxed. Under cooling at 0 ° C, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to obtain 1 benzyl-4,4-difluoropiperidine (4.67 g, 84%) as an oil. Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 1. 93— 2. 04 (4Η, m), 2. 53— 2. 55 (4Η,

 Three

 m), 3.54 (2H, s), 7.24—7.34 (5H, m).

EI-MSm / z: 211 (M ⁺ ).

[0221] 2) Title compound

 In an argon atmosphere, add 1-chlorodiethyl formic acid (2.62 ml) dropwise at 0 ° C to a solution of benzene 4, 4-difluoropiperidine (4.66 g) in dichloromethane (93 ml) at 0 ° C. Thereafter, the mixture was heated to reflux for 2 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, and a solution of the resulting residue in methanol (93 ml) was heated to reflux for 4 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, and then the resulting residue was added with jetyl ether, and the precipitated solid was collected by filtration to obtain the title compound (3.03 g, 87%).

 'H-NMR (400MHz, D Ο) δ: 2. 31— 2. 41 (4H, M), 3. 43— 3. 46 (4H, m

 2

 ) ·

FAB MSm / z: 122 (M + H) +. [0222] [Reference Example 19] 4-Full-year-old lopiperidine hydrochloride

[0223] [Chemical 31]

■ HCI

[0224] 1) 4-Fluoropiperidine 1 Carboxylic acid tert butyl ester

 [Bis (2-methoxyethyl) amino] sulfur trifluoride (7) in a solution of 4-hydroxypiperidine, 1-strength rubonic acid tert-butyl ester (4.00 g) in dichloromethane (80 ml) under an argon atmosphere, and cooled to 78 ° C. 33 ml) was added dropwise, stirred for 30 minutes, then stirred at 0 ° C for 30 minutes, and further stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formyl acetate) and 4-fluoropiperidine 1 carboxylic acid tert-butyl ester (1.777 g, 44% ) Was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.45 (9Η, s), 1.76— 1.86 (4Η, m), 3.4

 Three

 1-3. 54 (4H, m), 4. 70--4. 87 (1H, m).

 EI— MSmZz: 203 (M +).

[0225] 2) Title compound

 To a solution of the above 4 fluoropiperidine 1 carboxylic acid tert butyl ester (1.74 g) in dichloromethane (35 ml), 4N hydrochloric acid-dioxane solution (12 ml) was added at room temperature and stirred for 40 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the residue obtained was added with jetyl ether, and the precipitated solid was collected by filtration to obtain the title compound (0.870 g, 73%).

 'H-NMR (400MHz, DMSO- d) δ: 1. 92— 2. 13 (4Η, m), 3. 01— 3. 12 (

 6

 4mm, m), 4.83-4.97 (1mm, m).

 FAB MSm / z: 104 (M + H) +.

[0226] [Reference Example 20] Hexahydropyridazine hydrochloride

[0227] [Chemical 32] , -xHCI

 HN)

 N—

 H

[0228] 1) 3, 6 Dihydropyridazine 1, 2 Dicarboxylic acid = Dibenzyl ester

 1,3-Butadiene (14.2 g) was blown into a solution of 1,2 diazodicarboxylic acid = dibenzyl ester (10.28 g) in benzene (50 ml) under cooling at −10 ° C., and then stirred at room temperature for 16 hours. The reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane). 3,6 Dihydropyridazine 1,2 dicarboxylic acid = dibenzyl ester (2.57 g, 21%) was oily Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 3. 70— 3. 85 (2Η, br), 4. 35—4.52 (2Η,

 Three

 br), 5. 05- 5. 25 (4H, br), 5. 78 (2H, br), 7.03-7.40 (10H, m).

 FAB— MSm / z: 353 (M + H) +.

[0229] 2) Hexahydropyridazine

 To a solution of 3,6 dihydropyridazine 1,2 dicarboxylic acid = dibenzyl ester (2.57 g) in methanol (25 ml), add 10% palladium on carbon (0.754 g) and stir for 19 hours in the presence of hydrogen. did. After removing the catalyst from the reaction solution by filtration, the filtrate solvent was distilled off under reduced pressure to obtain hexahydropyridazine (0.629 g, quantitative) as an oil.

 'H-NMR (400MHz, DMSO- d) δ: 1. 67—1. 75 (2Η, m), 1. 96— 2. 05 (

 6

 2mm, m), 2.60-3.10 (4H, m).

ESI-MSm / z: 87 (M + H) ⁺ .

[0230] 3) Hexahydropyridazine 1-strength rubonic acid tert butyl ester

 Method A)

 To a solution of hexahydropyridazine (0.72 g) in methanol (20 ml) was added di tert-butoxydicarbonate (2.10 g) at room temperature, and the mixture was stirred for 15 hours. The reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone monochloroform). Hexahydropyridazine 1 rubonic acid tert butyl ester (0.671 g, 43%) was oily. Obtained as a thing.

'H-NMR (400MHz, CDC1) δ: 1.48 (9Η, s), 1.50—1.73 (4Η, m), 2.8 7 (2H, t like, J = 4.5 Hz), 3.51 (2H, t like, J = 4.5 Hz), 4.65 (1H, br). B method)

 To a solution of 2- (tert-butoxycarbol) hexahydropyridazine mono 1-carboxylic acid benzyl ester (Bioorg. Med. Chem., 2002, 10, 953, 26. 94 g) in methanol (250 ml), 10 % Palladium on carbon (50% wet, 5.21 g) was added and stirred for 4 hours in a hydrogen atmosphere. After separation by filtration, the solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-methanol) to give hexahydropyridazine mono 1-carboxylic acid tert butyl ester (18. 24 g, 85%) was obtained as an oil.

 'H-NMR (400MHz, CDC13) δ: 1. 48 (9Η, s), 1. 50—1.73 (4H, m), 2. 8 7 (2H, t like, J = 4.5 Hz), 3.51 (2H, t like, J = 4.5 Hz)

 4) Title compound

 To a solution of hexahydropyridazine 1 rubonic acid tert butyl ester (0.671 g) in dichloromethane (8 ml) was added 4N hydrochloric acid-dioxane solution (4 ml) at room temperature and stirred for 1 hour. Jetyl ether and pentane were added to the reaction solution, and the supernatant was removed by decantation. The residue was dried under reduced pressure to give the title compound (0.292 g, 66%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.66 (2Η, br), 2.50 (2Η, br), 2.98

 6

 (2H, br), 4. 35 (4H, br).

ESI-MSm / z: 87 (M + H) ⁺ .

[0231] [Reference Example 21] 1-Methylbiperazine mono 2-one hydrochloride

[0232] [Chemical 33]

■ HGI

 / ~ ゝ

 HN N—

0

[0233] 1) 3-Oxopiperazine 1 A strong rubonic acid tert butyl ester

Piperazine-2-one (2.5 g) in tetrahydrofuran (50 ml) and methanol (50 ml) mixed solution is mixed with triethylamine (3.83 ml) and di-tert-butoxy dicarbonate (6.32 ml). Was added at room temperature and stirred for 4 hours. The reaction solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the resulting residue for liquid separation. The organic layer was washed with water and saturated brine in this order, and then the washed water layers were combined and extracted again with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was solidified with ethyl acetate-hexane to give 3-oxopiperazine 1-strength rubonic acid tert-butyl ester (3.6 g, 72%).

'H-NMR (400MHz, CDC1) δ: 1.48 (9Η, s), 3.37—3.40 (2Η, m), 3.6

 Three

 2- 3.65 (2H, m), 4.01 (2H, s), 6.32 (1H, br s).

[0234] 2) 4-Methyl-3-oxopiperazine 1 Carboxylic acid tert-Butyl ester

 After adding sodium hydride (60%, 960 mg) at 0 ° C to a solution of 3-oxopiperazine-1 ol uronic acid tert butyl ester (3. Og) in N, N-dimethylformamide (50 ml) To the reaction solution, methyl iodide (2.33 ml) was added and stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution for liquid separation. The organic layer was washed with water and then saturated brine, and the combined washed water layer was extracted again with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4-methyl-3-year-old kisopiperazine-1 carboxylic acid tert butyl ester (2. 32 g, 72%) as an oily substance.

 'H-NMR (400MHz, CDC1) δ: 1.47 (9Η, s), 3.01 (3Η, s), 3.34 (2H, t

 Three

 , J = 5.6Hz), 3.65 (2H, t, J = 5.6Hz), 4.07 (2H, s).

[0235] 3) Title compound

 A 4N hydrochloric acid-dioxane solution (20 ml) was added to the above 4 methyl 3oxopiperazine 1 carboxylic acid tert butyl ester (2.06 g), and the mixture was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off azeotropically under reduced pressure. The resulting residue was dried to obtain the title compound (1.44 g, 99%) as an oily substance.

 'H-NMR (400MHz, DMSO-d) δ: 2.86 (3Η, s), 3.34 (2Η, br m), 3.

 6

 50 (2H, m), 3.64 (2H, s).

 MS (ESI) m / z: 115 (M + H) +.

[0236] [Reference Example 22] 1-Methylbiperazine 2 on trifluoroacetate

Reference Example 21 2) 4 methyl 3-oxopiperazine 1 tert-butyl carboxylate Trifluoroacetic acid (3 ml) was added to a dichloromethane (6 ml) solution of the ester (0.308 g) at room temperature and stirred for 1.5 hours. The reaction solvent was evaporated under reduced pressure, and the resulting residue was dried to give the title compound (0.485 g, quantitative).

 'H-NMR (400MHz, CDC1-CD OD (15: l)) δ: 2.98 (3H, s), 3.39 (2H

 3 3

 , t—like, J = 6.1Hz), 3.54 (2H, t—like, J = 6.1Hz), 3.72 (2H, s).

MS (El) m / z: 114 (M ⁺ ).

[0237] [Reference Example 23] 4-Methoxypiperidine hydrochloride

[0238] [Chemical 34]

[0239] 4-methoxypiperidine of Reference Example 17 1) 1-strength rubonic acid tert butyl ester (5.34g) in 1,4 dioxane (10ml) solution was added 4N dioxane solution (10m 1) at room temperature. Stir for 30 minutes. Further, 4N hydrochloric acid-dioxane solution (20 ml) was added and stirred for 30 minutes. The reaction solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration with ethyl acetate to obtain the title compound (3.55 g).

 'H-NMR (400MHz, DMSO-d) δ: 1.68 (2Η, m), 1.93 (2Η, m), 2.91 (

 6

 2H, m), 3.08 (2H, m), 3.23 (3H, s), 3.42 (1H, q, J = 3.90Hz).

[0240] [Reference Example 24] (3S) 3 Fluoropyrrolidine hydrochloride

[0241] [Chemical 35]

 [0242] 1) (3S) 3 Fluoropyrrolidine 1 One strength rubonic acid tert butyl ester

(3R) -3 Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g) in dichloromethane (50 ml) was added with jetylaminosulfur trifluoride (2.22 ml) at -78 ° C and stirred at room temperature for 75 minutes. did. The reaction solution was poured into ice water and separated, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was washed with silica gel. Purification by column chromatography (hexane ethyl acetate) gave (3S) -3-fluoropi oral lysine 1 rubonic acid tert butyl ester (676 mg, 26%) as an oily substance.

 'H-NMR (400MHz, CDC1) δ: 1.45 (9Η, s), 2.17— 2.26 (1Η, m), 3.5

 Three

 2- 3.68 (5H, m), 5.20 (1H, dt, J = 52.7, 3.4 Hz).

[0243] 2) Title compound

 To a solution of the above (3S) -3 fluoropyrrolidine 1 rubonic acid tert butyl ester (600 mg) in dichloromethane (10 ml) was added 4N dioxane hydrochloride (5 ml) at room temperature and stirred for 75 minutes. Jetyl ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (341 mg, 86%).

 'H-NMR (400MHz, DMSO-d) δ: 2. 00— 2. 26 (2Η, m), 3. 15— 3. 56 (

 6

 4mm, m), 5.43 (1H, dt, J = 52. 9, 3. 8Hz), 9.83 (2H, br s).

[0244] [Reference Example 25] 4-Fluoromethylpiperidine hydrochloride

[0245] [Chemical 36]

[0246] 1) 4-Fluoromethylpiperidine 1 Carboxylic acid tert butyl ester

 4-Hydroxymethylpiperidine 1 Carboxylic acid tert-butyl ester (1.17 g) in dichloromethane (8 ml) under ice-cooling [bis (2-methoxyethyl) amino] sulfur trifluoride (1.2 ml) and [bis (2 [Methoxyethyl) amino] sulfur trifluoride (50% tetrahydrofuran solution, 3 ml) was added dropwise, and the mixture was stirred at room temperature for 17 hours. Water, saturated aqueous sodium hydrogen carbonate, and ethyl acetate were separated into the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate). 4 Fluoromethylpiperidine 1 carboxylic acid tert butyl ester (597 mg, 51%) was solid. Got as.

 'H-NMR (400MHz, CDC1) δ: 1. 22 (2Η, m), 1. 46 (9Η, s), 1. 70 (2H, d

 Three

, J = 12. 94Hz), 1.83 (1H, m), 2.71 (2H, br), 4.13 (2H, br), 4.21 (1H, d, J = 6.10Hz),

 4.32 (1H, d, J = 6.10Hz).

[0247] 2) Title compound

 4 Fluoromethylpiperidine (1) The title compound (526 mg, quantitative) was obtained as a solid in the same manner as in Reference Example 24 using 1-strength rubonic acid tert butyl ester (635 mg). 'H-NMR (400MHz, CDC1) δ: 1.76 (3Η, m), 1.96 (2Η, d, J = 13.4Hz)

 Three

 , 2.90 (2H, br), 3.54 (2H, d, J = 12.1 Hz), 4.26 (1H, d, J = 6. lOHz), 4.

37 (1H, d, J = 6. 10Hz).

[0248] [Reference Example 26] (3R) 3 fluoropiperidine hydrochloride

[0249] [Chemical 37]

[0250] [Method A]

 (2S) -2 Hydroxymethylpyrrolidine 1 Carboxylic acid tert butyl ester (3. Og) and Jetylamino sulfur trifluoride (2. 95 ml) were used in the same manner as 1) of Reference Example 24 to (3R) -3 Full Oropiperidine-1 carboxylic acid tert-butyl ester (346 mg) was obtained as an oil. This ester was dissolved in dichloromethane (20 ml), and 4 N hydrochloric acid-dioxane (7 ml) was stirred at room temperature for 30 minutes. Jetyl ether was removed from the reaction mixture, and the precipitate was collected by filtration to give the title compound (162 mg, 8% over 2 steps) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1. 65— 1. 93 (4Η, m), 3.03— 3. 20 (

 6

 4mm, m), 4.97 (1H, dd, J = 45. 7, 2. 4Hz), 9.34 (2H, br s).

 [0251] [Method B]

(2S) -1-Benzyl-2-hydroxymethylpyrrolidine (19. 89 g) in dichloromethane (300 ml) was charged with 0 ml of jetylaminosulfur trifluoride (20.6 ml) and stirred at room temperature for 90 minutes. . The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane). ) -1 benzyl 1-2 fluoromethylpyrrolidine and (3R) -1 benzyl 1-3 fluoropiperidine mixture (14. 56 g, 73%) was obtained as an oil. A solution of this mixture (7.25 g) and chloroformate 1 chloroethyl ester (4.50 ml) in dichloromethane (100 ml) was heated to reflux for 1.5 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol (5 Oml) and heated to reflux for 75 minutes. After air cooling, the reaction solvent was distilled off under reduced pressure, and the resulting residue was crystallized from methanol-jetyl ether to obtain the title compound (1.58 g, 30%).

 'H-NMR (400MHz, DMSO-d) δ: 1. 72—1.81 (4Η, m), 2. 91— 3.33 (

 6

 4Η, m), 4.98 (1Η, d, J = 46.1Hz), 9.33 (2H, s).

[0252] [Reference Example 27] (2S) 2 Fluoromethylpyrrolidine hydrochloride

[0253] [Chemical 38]

 [0254] 1) (2S) — 1 Benzoyl 2 Hydroxymethylpyrrolidine

 (2S) -2 Sodium bicarbonate (7.51 g) was added to a mixed solution of 2 hydroxymethylpyrrolidine (3.0 ml) and benzoyl chloride (6.92 ml) in dichloromethane (100 ml) and water (100 ml) at room temperature. Stir for 5 hours. Dichloromethane was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (120 ml) and water (60 ml), and lithium hydroxide monohydrate (6.25 g) was added to the reaction solution at room temperature and stirred overnight. did. The reaction solution was separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain (2S) -1 monobenzoyl-2-hydroxymethylpyrrolidine (5.79 g, 98%) as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 60— 2. 27 (4Η, m), 3. 43— 3.52 (2Η,

 Three

 m), 3.71-3.82 (2H, m), 4.40 (1H, d, J = 7.3Hz), 4.92 (1H, s), 7.40-7.52 (5H, m).

[0255] 2) (2S) — 1 Benzoro 2 Fluoromethylpyrrolidine

(2S) -1-Benzyl 2-hydroxymethylpyrrolidine (1.50 g) in dichloromethane (5 To the solution (Oml), jetylaminosulfur trifluoride (1.93 ml) was added under ice-cooling and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) (2S) -1 monobenzoyl 2 fluoromethylpyrrolidine (772mg, 51%) Was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 74— 2. 18 (4Η, m), 3. 49 (2Η, br s),

 Three

 4. 44—4. 90 (3H, m), 7. 38— 7. 54 (5H, m).

[0256] 3) (2S) — 1 Benjirou 2 Fluoromethylpyrrolidine

 Under a nitrogen atmosphere, lithium aluminum hydride (128 mg) was added to a tetrahydrofuran (20 ml) solution of (2S) -1 monobenzoyl 2 fluoromethylpyrrolidine (350 mg) at room temperature and heated to reflux for 1 hour. After air cooling, ice was added to the reaction solution to treat excess lithium aluminum hydride, and then the reaction solution was separated by adding jetyl ether and water, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate hexane) to give (2S) -1 benzyl 2-fluoromethylpyrrolidine (142 mg, 44%) as an oil. It was.

 'H-NMR (400MHz, CDC1) δ: 1. 62—1. 76 (3Η, m), 1. 88— 1. 97 (1Η,

 Three

 m), 2. 25- 2. 31 (1Η, m), 2. 84— 2. 97 (2H, m), 3. 48 (1H, d, J = 12.9H z), 4.04 (1H , d, J = 13.2Hz), 4.21-4.4.2 (2H, m), 7.22--7.34 (5H, m).

 [0257] 4) Title compound

 To a solution of (2S) -1-benzyl-2-fluoromethylpyrrolidine (466 mg) in dichloromethane (20 ml), 1-chloroethyl phthalate (289 1) was heated at reflux at room temperature for 1 hour. After air cooling, the reaction solvent was evaporated under reduced pressure, and the resulting residue was dissolved in methanol (20 ml) and heated to reflux for 1 hour. After cooling with air, the reaction solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration with jetyl ether to give the title compound (292 mg, 87%).

 'H-NMR (400MHz, DMSO-d) δ: 1. 56— 2. 06 (4Η, m), 3. 15 (2Η, t, J

 6

 = 7.2Hz), 3.75-3.85 (1H, m), 4.55—4.76 (2H, m), 9.66 (2H, s).

[0258] [Reference Example 28] 3-Methoxypiperidine hydrochloride [0259] [Chemical 39]

■ HCI

 Olvle

[0260] 1) 3 Hydroxypiperidine 1 Powerful rubonic acid tert butyl ester

 3 To a solution of hydroxypiperidine (5.00 g) in methanol (50 ml) was added a solution of triethylamine (15.2 ml) and ditertbutoxydicarbonate (11.9 g) in methanol (50 ml) at room temperature, and the mixture was stirred for 15 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform). 3-Hydroxypiberidine 1-strength rubonic acid tert butyl ester (9.86 g, 99%) Was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.36— 1.55 (2Η, m), 1.45 (9Η, s), 1.7

 Three

 1- 1.78 (1H, m), 1.88 (1H, m), 3.02-3.13 (2H, m), 3.52 (1H, m), 3.72-3.76 (2H, m).

 EI— MSmZz: 201 (M +).

[0261] 2) 3-Methoxypiperidine 1Rubon acid tert butyl ester

 3-Hydroxypiperidine 1 Powered norebonic acid tert-Butinoreestenole (9.86 g) and Miso methyl (3.66 ml) were used in the same manner as 1) of Reference Example 17 to produce 3-methoxypiperidine 1 Strong rubonic acid tert butyl ester (9.24 g, 88%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.30—1.54 (2Η, m), 1.46 (9Η, s), 1.7

 Three

 2- 1.73 (1H, m), 1.92 (1H, m), 3.04— 3.21 (3H, m), 3.37 (3H, s), 3.55-3.74 (2H, m).

EI-MSm / z: 215 (M ⁺ ).

[0262] 3) Title compound

 3-Methoxypiperidine 1 The title compound (6.36 g, 98%) was obtained as a solid in the same manner as in Reference Example 19 2) using 1-strength rubonic acid tert-butyl ester (9.24 g). 'H-NMR (400MHz, DMSO-d) δ: 1.58— 1.61 (2Η, m), 1.76—1.81 (

 6

2Η, m), 2.88-2.94 (3Η, m), 3.09—3.13 (1H, m), 3.28 (3H, s), 3.5 5- 3. 51 (1H, m).

EI-MSm / z: 115 (M ⁺ ).

[0263] [Reference Example 29] (2S, 5R) -2-Methoxymethyl-5-methylpyrrolidine hydrochloride

[0264] [Chemical 40]

■ HGI

 [0265] 1) (2S, 5S) 2- (4 Methylphenol) sulfoloxymethyl-5-methoxypyrrolidine 1 Carboxylic acid tert butyl ester

Under ice-cooling, (2S, 5S) -2 benzyloxymethyl-5-hydroxymethylpyrrolidine 1-carboxylic acid tert-butyl ester (3.04 g, S. Takano et al., Tetrahedron Lett., 1989, 30, 3805-3806) Sodium hydride (60% in oil, 568 mg) was stirred for 30 minutes at room temperature in a solution of Tobi-Metinore (lml) in Ν, Ν Dimethinolehonolemamide (30 ml). Water and jetyl ether were added to the reaction solution for separation, and the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) (2S, 5S) -2 benzyloxymethyl 5-methoxymethylpyrrolidine 1 carboxylic acid tert-butyl Luster (2.68 g, 85%) was obtained as an oil. Metanonore (50ml) solution [this the 5-methoxymethyl-pyrrolidine body ^{(2. 68g), 10 0/} 0 Norajiumu carbon _{^{(50 0/0 wet, 1.}} 50g) and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration of the reaction solution, the filtrate solvent was distilled off under reduced pressure to obtain (2S, 5S) 2 hydroxymethyl-5-methoxymethylpyrrolidine-1 rubonic acid tert butyl ester (1.92 g, 98%) as an oil. It was. To a solution of this 2-hydroxymethylpyrrolidine (1.44 g) and p-toluenesulfuryl chloride (1.34 g) in dichloromethane (50 ml) was added pyridine (5 ml) at room temperature and stirred overnight. 1N Hydrochloric acid and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol-chloroform) (2S, 5S) 2- (4 methylphenol) sulfo-loxymethyl-5 -Methoxypyrrolidine 1 ol uronic acid tert butyl ester (1.64 g, 70%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 35 and 1. 43 (9Η, s), 1. 80— 2. 10 (4

 Three

 H, m), 2. 44 and 2. 45 (3H, s), 3. 23— 3. 52 (2H, m), 3. 31 (3H, s), 3. 83 -4. 23 (4H, m), 7.34 (2H, t, J = 9.0 Hz), 7.78 (2H, t, J = 4.0 Hz).

 [0266] 2) Title compound

 Under a nitrogen atmosphere, add (2S, 5 S) -2- (4 methylphenol) sulfo-loxymethyl-5-methoxypyrrolidine-1 carboxylic acid tert-butyl ester (1.601 g) in dimethylsulfoxide (30 ml) at room temperature. Sodium borohydride (55% in oil, 313 mg) was added, and the mixture was stirred with heating at 85 ° C. for 1 hr. After air cooling, water and jetyl ether were separated into the reaction solution, and the organic layer was washed with water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dichloromethane (30 ml), 4N hydrochloric acid-dioxane (10 ml) was added at room temperature, and the mixture was stirred for 1.5 hours. The reaction solvent was evaporated under reduced pressure to give the title compound (216 mg, 33%) as a solid.

 ESI— MSm / z: 130 (M + H) +.

 [0267] [Reference Example 30] 1— (6-Methoxy-3-pyridyl) -5- (1H-pyrrole-3-yl) 1 H-pyrazole 3-carboxylic acid

 [0268] [Chemical 41]

1— [1 (Phenolsulfol) 1H Pyrrole-3yl] 1 Ethanone (10.7 g), Jetyl oxalate (8.60 ml), and Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran 4 [1— (Phenolsulfol) — 1H pyrrole—3—yl] —2, 4 Dioxobutanoic acid in the same manner as in Reference Example 8 3). Ethyl ester (12.4 g) was obtained as a solid. To a solution of this butyric acid ethyl ester (4.00 g) in ethanol (50 ml), 3 hydrazino 2-methoxypyridine (1.90 g) of Reference Example 2 and acetic acid (3.91 ml) were added at room temperature, and the mixture was heated to reflux overnight. Further, concentrated hydrochloric acid (1.00 ml) was added to the reaction solution, and the mixture was heated to reflux for 6 days. After cooling with air, the reaction solvent was evaporated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution, water and ethyl acetate were added to the residue, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. Ethanol (50 ml) and sodium hydroxide (816 mg) were added to the resulting residue at room temperature, followed by stirring for 3 hours. Further, water (20 ml) was added to the reaction solution and stirred overnight. The reaction solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane acetate ethyl) to give 1- (6-methoxy-3-pyridyl) -5- (1H pyrrole-3 —Yil) 1H-pyrazole-3-strong rubonic acid ethyl ester (21 Omg, 5%) was obtained. 'H-NMR (400MHz, CDC1) δ: 1.41—1.44 (3Η, t, J = 7.1Hz), 3.98 (3

 Three

 H, s), 4.45 (2H, q, J = 7.1Hz), 6.04— 6.09 (1H, m), 6.57— 6.60 (1H, m), 6.73-6.76 (1H, m), 6.80 (1H, d, J = 8.8Hz), 6.95 (1H, d, J = 0.7 Hz), 7.66 (1H, ddd, J = 8.8, 2.7, 0.7Hz), 8.25 (1H, d, J = 2.7Hz), 8. 34 ( 1H, br s).

 FAB— MSm / z: 313 (M + H) +.

[0270] The solid precipitated from the aqueous layer during the liquid separation operation was collected by filtration to give the title compound (1.60, 41%

)

 'H-NMR (400MHz, DMSO-d) δ: 3.89 (3Η, d, J = l.5Hz), 5.82 (1H,

 6

 d, J = l.5Hz), 6.53 (1H, d, J = l.5Hz), 6.61 (1H, s), 6.66— 6.73 (1H, m), 6.88 (1H, dd, J = 8.8, 1.0Hz ), 7.70 (1H, ddd, J = 8.7, 1.5, 1.5Hz

), 8.16-8.20 (1H, m), 11.14 (1H, s).

 FAB MSm / z: 285 (M + H) +.

[0271] [Reference Example 31] 1— (6-Methoxy-3-pyridyl) -5- (1-methyl-1H pyrazole

3 Hil) 1H Pyrazole-3-Power rubonic acid

[0272] [Chemical 42]

[0273] 1) 1-Methyl- 1H Pyrazole 3-Strong rubonic acid N-Methoxy-N-methylamide

 1-Methyl 1H pyrazole-3-carboxylic acid (2.025g) in dichloromethane (80ml) at room temperature with 1-hydroxybenzotriazole (2.37g), 1- (3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride Salt (6.79 g), triethylamine (13.4 ml) and N, O dimethylhydroxylamine hydrochloride (2.93 g) were added and stirred for 22 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone chlorohonolem), and 1-methinole-1H-pyrazolole-3-carboxylic acid N-methoxy-N-methylamide (2.78 g, (Quantitative) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 3.43 (3Η, br s), 3.75 (3H, s), 3.97 (3H

 Three

 , s), 6.76 (1H, d, J = 2.4Hz), 7.36 (1H, d, J = 2.4Hz).

 FAB MSm / z: 170 (M + H) +.

[0274] 2) 3-asechinole-1-methinole -1H-pyrazonole

 1-Methyl 1 H Pyrazole 3 Carboxylic acid N-Methoxy-1-N-methylamide (2.78 g) and methyllithium (0.98M jetyl ether solution, 23 ml), the same method as in Reference Example 8-2) Gave 3acetyl-1-methyl-1H pyrazole (2.03 g, quantitative) as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.57 (3Η, s), 3.97 (3Η, s), 6.77 (1H, d

 Three

 , J = 2.4Hz), 7.37 (1H, d, J = 2.4Hz).

 EI-MSm / z: 124 (M +).

[0275] 3) 4- (1-Methyl 1H pyrazol-3-yl) 2, 4 Dioxobutanoic acid methyl ester — Lithium bis (trimethylsilyl) amide (1. OM in tetrahydrofuran solution, 20 ml) was added dropwise to a tetrahydrofuran (50 ml) solution of 3-acetyl-1-methyl-1H pyrazole (2.03 g) under cooling at 78 ° C. And stirred for 1 hour. A solution of dimethyl oxalate (3.90 g) in tetrahydrofuran (15 ml) was added dropwise to the reaction mixture, and the mixture was stirred at 0 ° C. for 2 hr. Water and diethyl ether were vigorously separated into the reaction solution, and the aqueous layer was acidified (pH 3) with 1N aqueous hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (1-methyl-1H-pyrazole-3-yl) -2,4-dioxobutanoic acid methyl ester (0.975 g, 28%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.85 (3Η, s), 3.92 (3Η, s), 6.88 (1H, br

 Three

 ), 7. 24 (1H, br), 7. 43 (1H, br). EI— MSm / z: 210 (M +).

[0276] 4) 1— (6-Methoxy-1-pyridyl) 5-— (1-Methyl 1H-pyrazole 3-yl)

 -1H-pyrazole 3 carboxylic acid methyl ester

 4- (1-methyl-1H pyrazole-3yl) -1,4-dioxobutanoic acid methyl ester (0.975 g) and 5-hydrazino-1-methoxypyridine (0.885 g) of Reference Example 2 in methanol (30 ml) Heated to reflux for 40 minutes. After air cooling, acetic acid (1.06 ml) was added to the reaction mixture, and the mixture was heated to reflux for 15 hours. After air-cooling, the reaction solvent was distilled off under reduced pressure, and Kuroguchi Form and saturated aqueous sodium hydrogen carbonate solution were added to separate the solution, and the aqueous layer was extracted with Kuroguchi Formol-Methanol (10: 1). The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone monochloroform). 1- (6-Methoxy-1-pyridyl)-5-(1-methyl-1H Pyrazol-3-yl) -1H pyrazole-3-carboxylic acid methyl ester (0.665 g, 46%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.88 (3Η, s), 3.96 (3Η, s), 3.97 (3H, s)

 Three

 , 5. 93 (1H, d like, J = 2.2 Hz), 6. 78 (1H, d, J = 8.5 Hz), 7. 20 (1H, s lik e), 7. 28- 7. 30 (1H, m), 7. 65— 7. 72 (1H, m), 8. 21 (1H, d, J = 2.5 Hz)

FAB-MSm / z: 314 (M + H) +.

[0277] 5) Title compound 1- (6-Methoxy-1-pyridyl) -5- (1-methyl-1H pyrazole-1-yl) -1H pyrazole-3-carboxylic acid methyl ester (0.665 g) in tetrahydrofuran (8 ml) and methanol (4 ml) Lithium hydroxide monohydrate (0.0955 g) was added to a mixed solution of water (4 ml) at room temperature and stirred for 2 hours. The reaction solvent was evaporated under reduced pressure, 1N aqueous hydrochloric acid solution was added to the resulting residue to make it acidic (PH4), and the precipitated solid was collected by filtration to give the title compound (0.348 g, 55%).

 'H-NMR (400MHz, DMSO-d) δ: 3.78 (3Η, s), 3.91 (3Η, s), 6.07—

 6

 6.13 (1H, m), 6.94 (1H, d, J = 8.8Hz), 7.07 (1H, s like), 7.69 (1H, s like), 7. 76- 7. 82 (1H, m), 8.21-8.25 (1H, m).

 FAB MSm / z: 300 (M + H) +.

[0278] [Reference Example 32] 1— (6-Methoxy-3-pyridyl) -5- (1-Methyl-1H—Pyrroyl 3-yl) 1H Pyrazole-3-Strong rubonic acid

[0279] [Chemical 43]

[0280] 1) 1— (6-Methoxy-1-pyridyl) -5- (1-methyl-1H pyrrole-3-yl) 1H-pyrazole 3 carboxylic acid ethyl ester

Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 11.1 ml) was added dropwise to a tetrahydrofuran (10 ml) solution of 3 acetyl-1-methylbilol (1.2 ml) at 78 ° C. and stirred for 30 minutes. To the reaction solution was added dropwise ethyl oxalate (2.06 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 3-methoxy-6hydrazinopyridine (2.50 g) of Reference Example 2, acetic acid (0.6 ml) and ethanol (50 ml) were added, and the mixture was heated to reflux for 18 hours. After cooling with air, a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexyl monoacetate) 1— (6— Methoxy-3-pyridyl) -5- (1-methyl 1H pyrrole-1-yl) 1H pyrazo 1-lu 3-force ruvic acid ethyl ester (2.45 g, 73%) was obtained as an oil.

 'H-NMR (400MHz, DMSO-d) δ: 1.41 (3Η, t, J = 7.20Hz), 3.59 (3H

 6

 , s), 3.98 (3H, s), 4.43 (2H, q, J = 7.20Hz), 5.91 (1H, dd, J = 2.81, 1.83Hz), 6.41 (1H, t, J = l.95Hz) , 6.51 (1H, t, J = 2.32Hz), 6.79 (1H, d, J = 8.79Hz), 6.90 (1H, s), 7.65 (1H, dd, J = 8.79, 2.69Hz), 8.25 (1 H , d, J = 2.32Hz).

[0281] 2) Title compound

 1- (6-Methoxy-1-pyridyl) -5- (1-methyl 1H pyrrole-1-yl) 1 H pyrazole-3-carboxylic acid ethyl ester (2.45 g) in tetrahydrofuran (30 ml) suspension in 1N at room temperature Sodium hydroxide aqueous solution (9 ml) was added and stirred for 16 hours. Further, 1N sodium hydroxide aqueous solution (4 ml) was stirred in the reaction solution for 3.5 hours. After the water and jetyl ether were vigorously separated into the reaction solution, the aqueous layer was made acidic with hydrochloric acid, extracted with black mouth form, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (1.53 g, 68%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.54 (3Η, s), 3.91 (3Η, s), 5.78 (1

 6

 H, dd, J = 2.69, 1.83Hz), 6.68 (1H, dt, J = 8.67, 2.56Hz), 6.84 (1H, s), 6.95 (1H, d, J = 8.79Hz), 7.77 (1H, dd , J = 8.89, 2.69Hz), 8.23 (1

H, d, J = 2.69Hz), 12.81 (1H, br).

 EI— MSmZz: 299 (M +).

[0282] [Reference Example 33] 1— (6-Methoxy-3 pyridazil) -5— (1H—Pyroleoyl 3 yl)

 -1H-pyrazole 3 carboxylic acid

[0283] [Chemical 44]

[0284] 3 ァセチルー 1 フエ-ルスルホ-ルビロール（2. 23g)、シユウ酸ジメチル（1. 6 Og)およびリチウムビス（トリメチルシリル）アミド（1. 0Mのテトラヒドロフラン溶液， 9. 8 5ml)とを用いて、参考例 31の 3)と同様の方法で、 4 [1 （フエ-ルスルホ -ル） 1H ピロール— 3—ィル]—2, 4 ジォキソブタン酸メチルエステル（1. 76g)を固 体として得た。

[0284] Using 3-acetyl-1-phenolsulfurubirol (2.23 g), dimethyl oxalate (1.6 Og) and lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 9.8 5 ml) 4 [1 (Phenolsulfol) 1H Pyrrole-3-yl] -2, 4 Dioxobutanoic acid methyl ester (1.76 g) was obtained in the same manner as in Reference Example 31 3). .

 A solution of this butanoic acid methyl ester (1.76 g) and 3 black mouth 6 hydrazinopyridazine (759 mg) in methanol (30 ml) was heated to reflux overnight. Concentrated hydrochloric acid (1.00 ml) was added to the reaction solution, and the mixture was further heated to reflux for 3 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution, water and ethyl acetate were added to the residue, the phases were separated, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (jetyl ether / dichloromethane). —Hil) 1H Pyrazolu lu 3-Carboxylic acid methyl ester and 1— (6-Methoxy-3 pyridazil) —5— (1H-pyrrole-3 yl)-1H-pyrazole 3 Carboxylic acid mixture (6- Black mouth pyridazine body: 6-methoxypyridazine body = 8: 1, 1.85 g) was obtained as a solid.

 To a mixed solution of this mixture (1.85 g) in methanol (30 ml) and tetrahydrofuran (50 ml), sodium methoxide (676 mg) was stirred at room temperature for 4 hours. Further, 1N aqueous sodium hydroxide solution (9. Oml) was stirred at room temperature overnight at room temperature. A 1N aqueous hydrochloric acid solution (22 ml) was added to the reaction solution, and then methanol and tetrahydrofuran as reaction solvents were distilled off under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (1.20 g, 47%).

 'H-NMR (400MHz, DMSO-d) δ: 4.44 (3Η, s), 6. 20— 6. 24 (1Η, m)

 6

 , 7. 02- 7. 06 (1H, m), 7. 09— 7. 12 (1H, m), 7. 26 (1H, d, J = 0.7 Hz), 7

82 (1H, dd, J = 9. 2, 0. 8Hz), 8. 14 (1H, dd, J = 9. 2, 0. 7Hz), 11. 36 (1

H, br s), 13. 29 (1H, br s).

 FAB MSm / z: 286 (M + H) +.

[0285] [Reference Example 34] 1— (6-Methoxy-3-pyridyl) -5- (1-methyl-1H-imidazole)

 4Hil) 1H Pyrazole-3-Power rubonic acid

[0286] [Chemical 45]

[0287] 1) 1-Methyl- 1H-imidazole- 4 Powerful rubonic acid N-methoxy-N-methylamide

 Using 1-methyl-1H-imidazole-4-carboxylic acid (1.26 g) and N, O dimethylhydroxylamine hydrochloride (1.17 g) in the same manner as 1) of Reference Example 31, 1 methyl-1H -Imidazole-4-carboxylic acid N-methoxy-N-methylamide (1.08 g, 64%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.45 (3Η, s), 3.73 (3Η, s), 3.78 (3H, s)

 Three

 , 7. 45 (1H, s), 7. 54 (1H, s).

[0288] 2) 4-Acetyl- 1-methyl- 1H-imidazole

 1-Methyl 1 H Imidazole 4 Carboxylic acid N-methoxy-N-methylamide (1.08 g) and methylolene lithium (0.98 M ethino-retenole solution, 6.84 ml) were used! In the same manner as in 2), 4-acetyl-1-methyl-1H-imidazole (309 mg, 39%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.56 (3Η, s), 3.75 (3Η, s), 7.44 (1H, s)

 Three

 , 7. 56 (1H, s).

 3) 1- (6-Methoxy-3 pyridyl) -5- (1-methyl-1H-imidazole-4-yl) 1H pyrazole 3 carboxylic acid ethyl ester

Under a nitrogen atmosphere, lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 2.71 ml) was added dropwise to a solution of 4-acetyl-1-methyl-1H-imidazole (306 mg) in tetrahydrofuran (25 ml) at -78 ° C cooling. Then, it was stirred for 30 minutes. To the reaction solution was added jetyl oxalate (5021), and the mixture was stirred at room temperature for 105 minutes. Ethanol (50 ml), 5-hydrazinone 2-methoxypyridine (343 mg) of Reference Example 2 and 1 M ethanol hydrochloride (2.71 ml) were added to the reaction mixture, and the mixture was heated to reflux overnight. After air cooling, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. Filter After separation, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate) to give 1- (6-methoxy-1-pyridyl) -5- (1-methyl-1H-imidazo (Lu 4-yl) -1H pyrazole-3-carboxylic acid ethyl ester (302 mg, 37%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.41 (3Η, t, J = 7.1Hz), 3.64 (3H, s), 3

 Three

 .98 (3H, s), 4.43 (2H, q, J = 7.1Hz), 6.55 (1H, s), 6.81 (1H, d, J = 8.8 Hz), 7.17 (1H, s), 7.41 (1H, s), 7.71 (1H, dd, J = 8.8, 2.7Hz), 8.24 (1H, d, J = 2.4Hz).

 ESI— MSm / z: 328 (M + H) +.

 [0289] 4) Title compound

 1- (6-Methoxy-3 pyridyl) -5- (1-methyl-1H-imidazole-4-yl) -1H-pyrazole 3 carboxylic acid ethyl ester (286 mg) in tetrahydrofuran (15 ml) and water (5 ml) To the mixture, lithium hydroxide monohydrate (llOmg) was added at room temperature and stirred overnight. A 1N aqueous hydrochloric acid solution (2.63 ml) and a mixed solvent of chloroformate-methanol (10 to 1) were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (184 mg, 70%) as a solid.

 ESI— MSm / z: 300 (M + H) +.

 [0290] [Reference Example 35] 3 Hydrazino 6-methylpyridazine

[0291] [Chem 46]

Hydrazine monohydrate (45 ml) was added to an ethanol (45 ml) suspension of 3-chloropyridazine 6-methylpyridazine (3. OOg), and the mixture was heated to reflux for 2.5 hours. After air-cooling, the solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (chromoform form methanol mono-water (lower layer solvent of 7: 3: 1 (νΖν)) to give the title compound ( 2.35 g, 81%) was obtained as a solid, 'H-NMR (400 MHz, DMSO-d) δ: 2.39 (3 Η, s), 4.20 (2 Η, br), 6.94 (

 6

1H, d, J = 9.3Hz), 7.18 (1H, d, J = 9.3Hz), 7.64 (1H, br). ESI-MSm / z: 125 (M + H) ⁺ .

[0293] [Reference Example 36] 1— (6-Methyl-3 pyridazil) 5— (1-Methyl-1H pyrrole)

 3 Hil) 1H Pyrazole-3-Power rubonic acid

[0294] [Chemical 47]

[0295] 1) 1- (6-Methyl-3 pyridazil) -5- (1-Methyl- 1H-Pyrroyl 3-yl)-1H Pyrazole 3 Carboxylic acid methyl ester

 Reference Example 14 1) -4) (1-methyl-1H-pyrrole 3-yl) -2,4 dioxobutanoic acid methyl ester (3.49 g) and Reference Example 35 6-methyl 3 hydrazinopyridazine (2.30 g) ) And 1 (6-Methyl-3 pyridazyl) -5- (1-Methyl-1H pyrrole-3-yl) —1H Pyrazole-3-Carbon The acid methyl ester (4.14 g, 70%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.79 (3Η, s), 3.62 (3Η, s), 3.96 (3H, s)

 Three

 , 6.08-6.13 (1H, m), 6.53 (1H, t, J = 2.7Hz), 6.92— 6.97 (1H, m), 6.95 (1H, s), 7.48 (1H, d, J = 8.8Hz ), 7.76 (1H, d, J = 8.8Hz).

 FAB MSm / z: 298 (M + H) +.

[0296] 2) Title compound

 1 (6-Methyl-3 pyridazil) -5- (1-Methyl-1H-Pyrroyl 3-yl)-1H Pyrazole-3-carboxylic acid methyl ester (4.14 g) and lithium hydroxide monohydrate (0.656 g ) To give the title compound (3.07 g, 78%) as a solid in the same manner as in Reference Example 14 3).

 'H-NMR (400MHz, DMSO-d) δ: 2.73 (3Η, s), 3.55 (3Η, s), 5.79—

 6

5.84 (1H, m), 6.66 (1H, t like, J = 2.0Hz), 6.81 (1H, t like, J = 2.0Hz), 6.91 (1H, s), 7.85 (2H, s). ESI— MSm / z: 284 (M + H) +.

[0297] [Reference Example 37] 5- (5 cyano-2-pyridyl) -1 (6-methyl-3-pyridyl) -1H pyrazonole 3-force norebonic acid

[0298] [Chemical 48]

[0299] 1) 5 Benzyloxy-2-methylpyridine

 5 Benzyl bromide (10.9 ml) was stirred in a solution of hydroxy-2-methylpyridine (10. Og) and potassium carbonate (38.0) in acetonitrile (200 ml) at room temperature for 12 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 5 benzyloxy-2-methylpyridine (4.14 g, 23%) as an oil. It was.

 'H-NMR (400MHz, CDC1) δ: 2.48 (3Η, s), 5.08 (2Η, s), 7.05 (1H, d

 Three

 , J = 8.5Hz), 7.16 (1H, dd, J = 8.5, 2.9Hz), 7.31- 7.43 (5H, m), 8.2 6 (1H, d, J = 2.9Hz).

EI-MSm / z: 199 (M ⁺ ).

[0300] 2) 1— (5 Benzyloxy-2-pyridyl) 1-ethanone

5 Selenium dioxide (9.20 g) was added to a solution of benzyloxy-2-methylpyridine (4.13 g) in pyridine (83 ml) at room temperature, and the mixture was heated to reflux for 61 hours. After air cooling, water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, N, O dimethylhydroxylamine hydrochloride (2.22 g), 1- (3 dimethylaminopropyl) 3 ethylcarbodiimide hydrochloride (4.37 g), To a solution of 1-hydroxybenzotriazole (3.08 g) in N, N dimethylformamide (95 ml), triethylamine (6.35 ml) was stirred at room temperature for 61 hours. Water and acetate Chill was added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 5-benzyloxypyridine 2 carboxylic acid N-methoxy-1-N methylamide (3.75 g, 66%) was obtained as an oil. (FAB- MSmZz: 273 (M + H) +.) Under argon atmosphere at 0 ° C, 5 benzyloxypyridine 2-carboxylic acid N-methoxy-N-methylamide (3.74 g) in tetrahydrofuran (75 ml) Methyl lithium (1.1 OM in ethyl ether solution, 13.7 ml) was added dropwise and stirred for 40 minutes. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl hexyl acetate) to give 1- (5-benzyloxy-2-pyridyl) -1-ethanone (1.47 g, 47%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.67 (3Η, s), 5.18 (2Η, s), 7.30—7.45

 Three

 (6H, m), 8.03 (1H, d, J = 8.8Hz), 8.39 (1H, d, J = 2.7Hz).

EI-MSm / z: 227 (M ⁺ ).

3) 4— (5-Benzyloxy-2-pyridyl) 2, 4 Dioxobutanoic acid ethyl ester

 Under an argon atmosphere, sodium ethoxide (0.874 g) in ethanol (15 ml) was added with ethyl oxalate (1.75 ml) and the above 1 (5 benzyloxy-2 pyridyl) -1 ethanol (1.46 g) in ethanol. The solution (15 ml) was stirred at room temperature for 7 hours and then at 60 ° C. for 1 hour. After air cooling, sodium ethoxide (0.874 g) and ethyl oxalate (1.75 ml) were further stirred at 60 ° C. for 1 hour. After air cooling, water was added to the reaction solution, which was washed with a jetel ester, and a saturated salt / ammonium aqueous solution and black mouth form were separated into the aqueous layer. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give 4- (5-benzyloxy-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (1.38 g, 66%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1. 38— 1. 42 (3Η, m), 4. 35—4.42 (2Η,

 Three

m), 5.20 (2H, s), 7.35—7.44 (6H, m), 7.59 (1H, s), 8.14 (1H, d, J = 8.8Hz), 8 44 (1H, d, J = 2.7Hz) EI-MSm / z: 327 (M ⁺ ).

[0302] 4) 5- (5 Benzyloxy-2-pyridyl) 1- (6-methyl-3-pyridyl) 1H pyrazole 3-carboxylic acid ethyl ester

 Using 4- (5-benzyloxy-2-pyridyl) -2,4 dioxobutanoic acid ethyl ester (2.62 g) and 5-hydrazino 2-methylpyridine (0.986 g) of Reference Example 7 in the same manner as 4) of Reference Example 9 The method yielded 5- (5-benzyloxy-2pyridyl) 1- (6 methyl-3 pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (1.74 g, 52%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42 (3Η, t, J = 7.1Hz), 2.60 (3H, s), 4

 Three

.46 (2H, q, J = 7.1Hz), 5. 10 (2H, s), 7.19—7.42 (9H, m), 7.72 (1H, dd, J = 8.3, 2.4Hz), 8.26 (1H, d , J = 2.9Hz), 8.38 (1H, d, J = 2.4Hz) .F AB-MSm / z: 415 (M + H) ⁺ .

[0303] 5) 5- (5 Hydroxy-2-pyridyl) 1- (6-Methyl-3-pyridyl) 1H-virazole 3-carboxylic acid ethyl ester

 5- (5 Benzyloxy-2-pyridyl) 1- (6-methyl-3-pyridyl) 1H-pyrazole-3-strong rubonic acid ethyl ester (1.73 g) in ethanol (34 ml) and ethyl acetate (34 ml) mixed solution with 10% palladium Carbon (1.73 g) was added, and the mixture was stirred at room temperature in the presence of hydrogen gas for 3.5 hours. The reaction solution was filtered off, and the solvent of the obtained filtrate was distilled off under reduced pressure. 5-(5 Hydroxy1-2 pyridyl) 1- (6-methyl-3-pyridyl) 1H pyrazol luo 3-force ruvic acid ethyl ester (1.28 g, 95%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (3Η, t, J = 7.1Hz), 3.33 (3H,

 6

 s), 4.34 (2H, q, J = 7.1Hz), 7.18— 7.25 (2H, m), 7.34 (1H, d, J = 8.5 Hz), 7.51 (1H, d, J = 8.5Hz), 7.64— 7.67 (1H, m), 7.97 (1H, d, J = 2.9Hz), 8.35 (1H, d, J = 2.4Hz), 10.31 (1H, s).

 FAB MSm / z: 325 (M + H) +.

[0304] 6) Title compound

5— (5 Hydroxy-2-pyridyl) -1-1- (6-Methyl-3-pyridyl) 1H Pyrazole-3-Strong rubonic acid ethyl ester (1.27 g) in an argon atmosphere To a mixed solution of (25 ml) and pyridine (8.3 ml), trifluoromethanesulfonic anhydride (0.791 ml) was added dropwise at room temperature, followed by stirring for 1 hour. Further, trifluoromethanesulfonic anhydride (0.791 ml) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform). 1- (6 methyl-3-pyridyl) -5- (5 trifluoromethanesulfo-loxyl 2 Pyridyl) 1H Pyrazole-3-strong rubonic acid ethyl ester (1.77 g, 99%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42—1.45 (3Η, m), 2.63 (3Η, s), 4.4

 Three

 4—4. 50 (2H, m), 7. 24 (1H, d, J = 8.3 Hz), 7. 34 (1H, s), 7. 55— 7. 57 (1H, m), 7.65- 7. 70 (2H, m), 8.43— 8.45 (2H, m).

FAB MSm / z: 457 (M + H) +.

 Under an argon atmosphere, a suspension of tri-n-butyltin cyanide (4.88 g) and tetrakis (triphenylphosphine) palladium (0) (6.68 g) in dichloroethane (48 ml) was heated to reflux for 2 hours. 1- (6-Methyl-3-pyridyl) 5- (5 trifluoromethanesulfonyl-2-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (1.76 g) in dichloroethane (39 ml) was added dropwise to the reaction solution. The mixture was stirred at 80 ° C for 23 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was filtered through celite. Water and chloroform were added to the filtrate and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to give 5- (5 cyano-2-pyridyl) -1- (6-methyl-3pi Lysyl) -1H pyrazole-3-carboxylic acid ethyl ester (2.07 g) was obtained. To a suspension of the obtained ethyl ester in tetrahydrofuran (41 ml), a solution of lithium hydroxide monohydrate (0.162 g) in water (21 ml) was added dropwise at room temperature, followed by stirring for 1.5 hours. Water and black mouth form were added to the reaction solution to separate it. The aqueous layer was neutralized with 1N aqueous hydrochloric acid (3.86 ml), and the precipitated solid was collected by filtration to give the title compound (0.750 g, 64%) as a solid.

'H-NMR (400MHz, DMSO-d) δ: 2.54 (3Η, s), 7.36 (1Η, d, J = 8.3H

 6

z), 7.57 (1H, s), 7. 71-7. 73 (1H, m), 7.99 (1H, d, J = 8.3Hz), 8.40— 8.43 (2H, m), 8.84 (1H, d, J = l.2Hz), 13.20 (1H, br s).

 FAB MSm / z: 306 (M + H) +.

[0306] [Reference Example 38] 5- (3 formyl-1H-pyrrole-1-yl) -1 (6-methoxy-3-pyridyl) -1H-pyrazole 3 carboxylic acid ethyl ester

[0307] [Chemical 49]

[0308] In a solution of 5 amino 1- (6-methoxy-1-pyridyl) 1H pyrazol 3-strand rubonic acid ethyl ester (1.77 g) obtained in 1) of Reference Example 11 in acetic acid (35 ml), 2,5-dimethoxy Citetrahydro-1-furancarbaldehyde (1.62 g) was added, and the mixture was heated to reflux for 14.5 hours. After air cooling, the reaction solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the resulting residue for separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (1.38 g, 60%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.2Hz), 3.94 (3H, s), 4

 Three

 .47 (2H, q, J = 7.2Hz), 6.70— 6.71 (1H, m), 6.75— 6.77 (2H, m), 7.0

2 (1H, s), 7.28 (1H, dd, J = 2.2, 1.5Hz), 7.48 (1H, dd, J = 8.8, 2.8Hz)

, 8.02 (1H, dd, J = 2.8, 0.6Hz), 9.79 (1H, s).

ESI-MSm / z: 341 (M + H) ⁺ .

[0309] [Reference Example 39] 1— (6-Methoxy-3-pyridazil) -5- (5-methyl-2-pyridyl)

 -1H-pyrazole 3 carboxylic acid

[0310] [Chemical 50]

[0311] 1) 4— (5-Methyl-2-pyridyl)-2, 4 Dioxobutanoic acid methyl ester

 To a solution of sodium methoxide (4.74 g) in methanol (200 ml) was added dimethyl oxalate (10.4 g) at room temperature and stirred for 5 minutes. To the reaction solution, 1) (5-methyl-2-pyridyl) -1-ethanone (5.93 g) of 2) of Reference Example 15 was stirred at room temperature for 5 hours. Water and diethyl ether were vigorously separated into the reaction solution, and the aqueous layer was acidified with 1N aqueous hydrochloric acid and extracted with black mouth form. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (5-methyl-2-pyridyl) 2,4 dioxobutanoic acid methyl ester (7.31 g, 75%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.46 (3Η, s), 3.92 (3Η, s), 7.58 (1H, br

 Three

 ), 7.70 (1H, dd, J = 8. 06, 1. 83Hz), 8. 08 (1H, d, J = 8. 06Hz), 8. 54 (1 H, d, J = l. 22Hz ).

 [0312] 2) 1— (6-Methoxy-1-pyridazil) 5— (5-Methyl-2-pyridyl) 1H pyrazole 3-carboxylic acid ethyl ester

 4- (5-Methyl-2-pyridyl) -1,2,4 Dioxobutanoic acid methyl ester (3.34 g) in ethanol (200 ml) was added with 3 black mouth 6 hydrazinopyridazine (2.6 g) and heated for 1.5 hours. Refluxed. Concentrated hydrochloric acid (3 ml) was added to the reaction mixture, and the mixture was further heated to reflux for 4 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexyl monoacetate) to give 1— (6-methoxy-3-pyridazil) -5- (5— Methyl-2 pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (4.08 g, 82%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7. 08Hz), 2.41 (3H, s),

 Three

4. 48 (2H, q, J = 7. 08Hz), 7. 07 (1H, m), 7. 20 (1H, s), 7. 47 (1H, s), 7. 69 (1H, d, J = 9. 03Hz), 8. 08 (1H, d, J = 9. 03Hz), 8. 23 (1H, d, J = 4. 88 Hz).

 EI MSm / z: 344 (M + H) +.

[0313] 3) Title compound

 Sodium methoxide (1.3 g) in methanol (100 ml) at room temperature 1- (6-methoxy-3 pyridazil) -5- (5-methyl-2-pyridyl) -1H pyrazole 3-carbonic acid ethyl ester (4.08 g) was added and stirred for 21 hours. After the mixture was separated by adding jetyl ether and water to the reaction solution, a 1N hydrochloric acid aqueous solution was extracted into the aqueous layer with cake form, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 79%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.35 (3Η, s), 4.10 (3Η, s), 7.15 (1H, d

 Three

 , J = 9.28Hz), 7.23 (1H, s), 7.51 (1H, d, J = 7.93Hz), 7.60 (1H, d, J =

7.93Hz), 7.96 (1H, d, J = 9.28Hz), 8.32 (1H, s).

[0314] [Reference Example 40] 1— (6-Methyl-3 pyridyl) -5- (4-methyl-2-pyridyl) 1H pyrazonole 3-force norebonic acid

[0315] [Chemical 51]

[0316] 1) 1— (4-Methyl-2-pyridyl) 1-Ethanone

Under cooling at 78 ° C, n-butyllithium (1.58M hexane solution, 22 ml) was added dropwise to a solution of 2 bromo-4 picoline (4. Og) in ethyl ether (60 ml) over 5 minutes, then 5 minutes. Stir. N, N dimethylacetamide (3.3 ml) was added dropwise to the reaction solution, the temperature was gradually raised, and the mixture was stirred at room temperature for 14.5 hours. Water was poured into the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (4-methyl (Lu 2 pyridyl) 1-ethanone (1.86 g, 59%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 2.72 (3Η, s), 7.29 (1H, d

 Three

 d, J = 4.94, 0.67Hz), 7.86 (1H, d, J = 0.67Hz), 8.54 (1H, d, J = 4.94H z).

 [0317] 2) 4- (4-Methyl-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester

 1- (4-Methyl-2-pyridyl) 1-ethanone (1.86 g), sodium ethoxide (1.9 Og) and cetyl oxalate (3.74 ml) were used in the same manner as in Reference Example 9 3), (4-Methyl-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (3.82 g) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.38 (3Η, t, J = 7.08Hz), 2.51 (3H, s),

 Three

 4.36 (2H, q, J = 7.08Hz), 7.43 (2H, br), 8.03 (1H, s), 8.65 (1H, d, J =

5.01Hz).

 EI— MSm / z: 236 (M + H) +.

[0318] 3) 1- (6-Methyl-3-pyridyl) -5- (4-Methyl-2-pyridyl) 1H Pyrazol lu 3-carboxylic acid ethyl ester

 Using 4- (2-methyl-2-pyridyl) 2,4 dioxobutanoic acid ethyl ester (11.37 g) and 5-hydrazino 2-methylpyridine (6. Og) in Reference Example 7 in the same manner as in Reference Example 39 2) Thus, 1 (6-methyl-3-pyridyl) -5- (4-methyl-2-pyridyl) 1H pyrazole-3-strong rubonic acid ethyl ester (6.97 g, 45%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.43 (3Η, t, J = 7.08Hz), 2.35 (3H, s),

 Three

 2.59 (3H, s), 4.46 (2H, q, J = 7.08Hz), 7.05 (1H, d, J = 5.01Hz), 7.2 0 (1H, d, J = 8.30Hz), 7.24 (1H, s) , 7.26 (1H, s), 7.72 (1H, dd, J = 8.3 0, 2.44Hz), 8.33 (1H, d, J = 5.01Hz), 8.38 (1H, d, H = 2.44Hz).

EI-MSm / z: 323 (M + H) ⁺ .

[0319] 4) Title compound

1 (6-Methyl-3 pyridyl) -5- (4-Methyl 2 pyridyl) 1H Pyrazolux 3-Strong rubonic acid ethyl ester (6.97 g) and IN sodium hydroxide aqueous solution (24 ml) In the same manner as in Reference Example 3, 4), the title compound (5.26 g, 83%) was obtained as an amorphous substance.

 'H-NMR (400MHz, CDCl) δ: 2.37 (3Η, s), 2.61 (3Η, s), 7.08 (IH, d

 Three

 , J = 5.01Hz), 7.20 (IH, d, J = 8.30Hz), 7.27 (1H, s), 7.30 (1H, s), 7.73 (IH, dd, J = 8.30, 2.44Hz), 8.36 (IH, d, J = 5.01Hz), 8.45 (IH, d, J = 2.44Hz).

 EI— MSm / z: 295 (M + H) +.

[0320] [Reference Example 41] 1— (6-Methoxy-3-pyridyl) -5- (5-methyl-2-pyrazur)

1H-pyrazole 3 carboxylic acid

[0321] [Chemical 52]

[0322] 1) 1— (6-Methoxy-1-pyridyl) -5- (5-methyl-2-pyrazyl) 1H-virazole 3-carboxylic acid ethyl ester

 Using Reference Example 8-3) -4 (5-methyl-2-pyrazuryl) 2,4 dioxobutanoic acid ethyl ester (7.32 g) and Reference Example 2 5 hydrazino 2-methoxypyridine (4.31 g) 1 (6-Methoxy-3-pyridyl) -5- (5-methyl-2-pyrazuryl) 1H pyrazole-3-strong rubonic acid ethyl ester (4.80 g, 46%) was obtained as a solid by a method similar to 9-9).

 'H-NMR (400MHz, CDCl) δ: 1.41— 1.45 (3Η, m), 2.57 (3Η, s), 3.9

 Three

 6 (3H, s), 4.44—4.49 (2H, m), 6.79 (1H, dd, J = 8.8, 0.7Hz), 7.33 (1 H, s), 7.68 (1H, dd, J = 8.8, 2.7Hz ), 8.10- 8.11 (1H, m), 8.36 (1H, m), 8.54 (IH, d, J = l.5Hz).

 FAB-MSm / z: 340 (M + H) +.

[0323] 2) Title compound 1— (6-Methoxy-1-pyridyl) -5- (5-methyl-2-pyrazyl) 1H Pyrazo 1-lu 3-Strong rubonic acid ethyl ester (1.79 g) 4 of Reference Example 4 Method B) In the same manner as described above, the title compound (1.43 g, 87%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.50 (3Η, s), 3.90 (3Η, s), 6.90 (1

 6

 H, d, J = 8.8Hz), 7.47 (1H, s), 7.76 (1H, dd, J = 8.8, 2.7Hz), 8. 19 (1 H, d, J = 2.7Hz), 8.41 (1H, m), 8.85 (1H, d, J = l.5Hz), 13.12 (1H, br s).

 FAB— MSm / z: 312 (M + H) +.

[0324] [Reference Example 42] 5— (5-tert-butoxycarbolamino 2 pyrajur) -1 (6-methoxy 3 pyridyl) 1H pyrazole 3 carboxylic acid

[0325] [Chemical 53]

[0326] 1) 5- (5-Carboxy-2-pyridyl) -1- 1- (6-Methoxy-1-pyridyl) 1H-pyrazole 3-carboxylic acid ethyl ester

 In an argon atmosphere, in 1) of 1 (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyrazuryl) 1H-pyrazole-3-strong rubonic acid ethyl ester (3.00 g) in pyridine (60 ml) solution of Reference Example 41 Selenium dioxide (3.92 g) was added, and the mixture was heated to reflux for 23 hours. After air cooling, water and chloroform were added to the reaction solution, and the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to give 5- (5 carboxy-2-birazinyl) -1 (6 methoxy-3-pyridyl) 1H pyrazole 3 carboxylic acid ethyl ester (2.83 g, 87%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.35 (3Η, t, J = 7.1Hz), 3.92 (3H,

 6

s), 4.37 (2H, q, J = 7.1Hz), 6.92 (1H, d, J = 8.8Hz), 7.36—7.40 (1H, m), 7.76-7.84 (1H, m), 8.25 (1H, m), 8.96 (1H, d, J = l.5Hz), 9.18 (1H, d, J = l.5Hz).

 EI— MSmZz: 369 (M +).

[0327] 2) 5- (5-tert-Butoxycarbo-lamino-2-pyrazur) -1- 1- (6-Methoxy-1-pyridyl) 1H pyrazole 3 carboxylic acid ethyl ester

 Under argon atmosphere, a suspension of 5- (5 carboxy-2-pyrazuryl) -1 (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (2.81 g) in 1,4-dioxane (56 ml) at room temperature. Triethylamine (1.17 ml), diphenylphosphoryl azide (1.80 ml) and tert-butanol (1.60 ml) were stirred at 100 ° C for 25 minutes. After air cooling, the reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 5- (5-tert-butoxycarbo-lamino-2 pyridyl) -1- (6-Methoxy-1-pyridyl) 1H-pyrazole 1-3-carboxylic acid ethyl ester (1.29 g, 39%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42—1.45 (3Η, m), 1.54 (9Η, s), 3.9

 Three

 7 (3H, s), 4.44−4.50 (2H, m), 6.79 (1H, d, J = 8.8Hz), 7.28 (1H, s),

7.36 (1H, br s), 7.68 (1H, dd, J = 8.8, 2.9Hz), 8.11-8.12 (1H, m),

8.29 (1H, d, J = l.7Hz), 9.18 (1H, d, J = l.5Hz).

 EI MSm / z: 440 (M +).

 [0328] 3) Title compound

 5- (5-tert-Butoxycarbolamino-2-pyridyl) 1-1- (6-methoxy-1-3-pyridyl) -1H-pyrazole 3 carboxylic acid ethyl ester (1.28 g) ) To give the title compound (1.19 g, 99%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.48 (9Η, s), 3.91 (3Η, m), 6.90 (

 6

 1H, d, J = 8.8Hz), 7.41 (1H, m), 7.75— 7.78 (1H, m), 8.19 (1H, d, J = 2.7Hz), 8.62-8.63 (1H, m), 8.86— 8.87 (1H, m), 10.39 (1H, s), 13.10 (1H, br s).

EI-MSm / z: 412 (M +). [0329] [Reference Example 43] 5- (1H-imidazole-2-yl) -1 (6-methoxy-3-pyridyl)

-1H-pyrazole 3 carboxylic acid ethyl ester

[0330] [Chemical 54]

[0331] 1) 1 (1H-imidazole-2-yl) 1 Ethanone

 1-Diethoxymethyl 1H Imidazole (6.80 g) in tetrahydrofuran (100 ml) was cooled to 55 ° C. N-Butyllithium (1.58M hexane solution, 25.3 ml) was cooled to -35 ° C. While maintaining the following, the solution was added dropwise over 5 minutes and stirred at an internal temperature of −40 ° C. for 15 minutes. N, N dimethylacetamide (5.57 ml) was added dropwise to the reaction solution over 5 minutes, and the mixture was stirred at room temperature for 25.5 hours. Jetyl ether and 0.1N hydrochloric acid aqueous solution were added to the reaction solution, and the mixture was separated. The aqueous layer was neutralized with sodium bicarbonate and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 1- (1H-imidazol-2-yl) 1 -ethanone (3.06 g, 69%) as a solid.

 'H-NMR (400MHz, CD OD) δ: 2.56 (3H, s), 7.27 (2H, br s).

 Three

 ESI-MSm / z: 111 (M + H) +.

[0332] 2) 1— {1 [(4 Methylphenol) sulfol] 1H-imidazole 2-yl} 1 Ethanone

1- (1H-imidazole-2-yl) 1-ethanone (1. 10 g) in dichloromethane (10 ml) suspension was added triethylamine (2. 09 ml) and 4 methylbenzenesulfuryl chloride (2. 29 g). And stirred for 24.5 hours. Ethyl acetate and water were added to the reaction solution for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-dichloromethane). 1— {1— [(4-Methylphenol) sulfol] 1 H imidazole 2 yl} — 1-ethanone (2. 05 g, 77%) was obtained as a solid. 'H-NMR (400MHz, CDC1) δ: 2.44 (3H, s), 2.57 (3H, s), 7.17 (1H, d

 Three

 , J = l.5Hz), 7.36 (2H, d, J = 8.3Hz), 7.87 (1H, d, J = l.5Hz), 7.99 (2H, d, J = 8.3Hz).

 ESI— MSm / z: 265 (M + H) +.

[0333] 3) Title compound

 Under cooling at 78 ° C, 1 {1 [(4 Methylphenol) sulfol] 1H Imidazole — 2-yl} — 1-ethanone (1.91 g) in tetrahydrofuran (7.5 ml) was added to lithium bis (trimethylsilyl). Amide (1.OM in tetrahydrofuran, 7.95 ml) was added and stirred for 30 minutes. To the reaction mixture was added decyl oxalate (1.47 ml), and the mixture was stirred for 10 minutes, then gradually warmed up and stirred at room temperature for 3 hours. Jetyl ether and water were vigorously separated into the reaction solution, and the ether layer and 1N aqueous hydrochloric acid solution (7.95 ml) were added to the aqueous layer for separation. Further, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4 {1 [(4 methylphenol) sulfol] 1H-imidazol-2-yl} 2,4-dioxobutanoic acid ethyl ester. A solution of this ethyl ester and 5-hydrazino-1-methoxypyridine (1.00 g) of Reference Example 2 in ethanol (75 ml) was heated to reflux for 15.5 hours. After air cooling, the reaction solvent was removed downstream under reduced pressure. Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue for separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (0.210 g, 9.2%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42 (3Η, t, J = 7.1Hz), 3.96 (3H, s), 4

 Three

 .44 (2H, q, J = 7.1Hz), 6.78 (1H, d, J = 8.8Hz), 7.10 (2H, br s), 7.23 (1H, s), 7.68 (1H, dd, J = 8.8, 2.7Hz), 8.22 (1H, d, J = 2.7Hz), 9.60 (1H, br s).

 ESI— MSm / z: 314 (M + H) +.

[0334] [Reference Example 44] 3, 3 Difluoropyrrolidine hydrochloride

[0335] [Chemical 55]

[0336] 1) N— tert-Butoxycarbol 3 Pyrrolidinone

 (3R) —N— tert-butoxycarbol— 3 Hydroxypyrrolidine (2.47 g) and triethylamine (9.19 ml) in dimethyl sulfoxide (30 ml) at room temperature with pyridine. Sulfur trioxide (4.12 g) And stirred overnight. The reaction solution was poured into water and extracted with jetyl ether, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane), and N-tert-butoxycarboxyl 3 pyrrolidinone (855 mg, 34%) was obtained as an oil. Obtained.

 'H-NMR (400MHz, CDC1) δ: 1.47 (9Η, d, J = 9.3Hz), 2.59 (2H, t, J

 Three

 = 7.8Hz), 3.75-3.80 (4H, t, J = 7.9Hz).

[0337] 2) 3, 3 Difluoropyrrolidine 1

 Under a nitrogen atmosphere, N-tert-butoxycarbo-l 3 pyrrolidinone (846 mg) in benzene (30 ml) was added with ice-cooled (jetylamino) sulfur trifluoride (1.45 ml) and stirred at room temperature for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature overnight. Jetyl ether was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (ethyl hexane acetate). 3,3 difluoropyrrolidine-1-sulphonic acid tert butyl ester (669 mg, 71%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.45 (9Η, s), 2.26— 2.36 (2Η, m), 3.5

 Three

 7- 3.65 (4H, m).

[0338] 3) Title compound

3,3 Difluoropyrrolidine-1 Carboxylic acid tert-butyl ester (659 mg) was used in the same manner as in Reference Example 24, 2) to give the title compound (371 mg, 81%) as a solid. Ή-NMR (400MHz, DMSO d) δ: 2.42— 2.53 (2H, m), 3.39— 3.43 (

 6

 2H, m), 3.62 (2H, t, J = 12.6Hz), 10.17 (2H, s).

ESI-MSm / z: 108 (M + H) ⁺ .

[0339] [Reference Example 45] 5- (2-Methyloxazole-4-yl) 1 1 (6-Methyl-3 pyridyl) 1 1 H Pyrazole 3 Carboxylic acid

[0340] [Chemical 56]

[0341] 1) 2-Methyloxazole-4

 2-Methyloxazole-4-carboxylic acid methyl ester (2.63 g, DR Williams et al., Tetrahedron Lett., 1997, 38 (3), 331) in tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml ) Was mixed with lithium hydroxide monohydrate (0.867 g) at room temperature and stirred for 2 hours. The reaction solvent was distilled off under reduced pressure, and 1 N aqueous hydrochloric acid solution was added to the resulting residue (pH 4), and the precipitated solid was collected by filtration to give 2-methyloxazole-4 monostrept rubonic acid (0.987 g, 42%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.55 (3Η, s), 8.21 (1Η, s).

 Three

ESI-MSm / z: 128 (M + H) ⁺ .

[0342] 2) 4-Acetyl-2-methyloxazole

 2-Methyloxazole-4-Methyloxazole-In the same manner as 1) of Reference Example 31, using 1-strength rubonic acid (3.23 g) and N, O dimethylhydroxylamine hydrochloride (5.00 g) 4-Carboxylic acid N-methoxy-N-methylamide (4.32 g, quantitative) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.50 (3Η, s), 3.37 (3Η, s), 3.74 (3H, s)

 Three

 , 8.06 (1H, s).

EI-MSm / z: 170 (M +). Using this 2 methyloxazole 4 carboxylic acid N-methoxy N methylamide (4.2 3 g) and methyllithium (0.98M jetyl ether solution, 40 ml), Acetyl-2 methyloxazole (1.14 g, 37%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 2.50 (3Η, s), 2.51 (3Η, s), 8.10 (1H, s)

 Three

ESI-MSm / z: 126 (M + H) ⁺ .

[0343] 3) 4- (2-Methyloxazole 4-yl) 2, 4 Dioxobutanoic acid methyl ester

 Reference Example 31 3) using 4-acetyl-2-methyloxazole (1.14 g), lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 10. Oml) and dimethyl oxalate (2.15 g) In the same manner, 4- (2-methyloxazole-4-yl) 2,4-dioxobutanoic acid methyl ester (0.641 g) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.50 (3Η, s), 3.85 (3Η, s), 7.05 (1H, s)

 Three

 , 8.20 (1H, s).

ESI-MSm / z: 212 (M + H) ⁺ .

[0344] 4) 5- (2-Methyloxazole-4-yl) -1-(6-Methyl-3 pyridyl)-1H pyrazole 3-carboxylic acid methyl ester

 Reference example using 4- (2-methyloxazole-4-yl) -2,4 dioxobutanoic acid methyl ester (0.641 g) and 5-hydrazino-1-methylpyridine (0.459 g) from Reference Example 7 In the same manner as in 4) of 31, 5- (2-methyloxazole-4-yl) 1 (6-methyl-3-pyridyl) -1H pyrazole-3-carboxylic acid methyl ester (76.9 mg) as an oil Obtained.

 'H-NMR (400MHz, CDCl) δ: 2.44 (3Η, s), 2.65 (3Η, s), 3.96 (3H, s)

 Three

 , 7.18 (1H, s), 7.27-7.36 (2H, m), 7.72— 7.83 (1H, m), 8.56 (1H, d, J = 6.4Hz).

 FAB MSm / z: 299 (M + H) +.

[0345] 5) Title compound 5- (2-Methyloxazole-4-yl) -1 (6-Methyl-3-pyridyl) 1H-Pyrazol-3-Strong rubonic acid methyl ester (76.9 mg) and lithium hydroxide monohydrate (15.8 mg) The title compound (95.9 mg) was obtained as an oil in the same manner as in Reference Example 31 5).

 FAB MSm / z: 285 (M + H) +.

[0346] [Reference Example 46] 1-Methylbiperazine 2-one

[0347] [Chemical 57]

[0348] To a dichloromethane suspension of 1-methylbiperazine 2-one hydrochloride (19.6 g) of Reference Example 21 3), 1N aqueous solution of sodium hydroxide and sodium chloride was vigorously separated, and the aqueous layer was further separated. After saturated with sodium chloride, the mixture was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give the title compound (5.90 g) as an oil.

ESI-MSm / z: 115 (M + H) ⁺ .

 [0349] [Reference Example 47] 1— (6-Methoxy-3-pyridazil) -5- (5-methyl-2-pyrazuryl) — 1H Pyrazole 3 carboxylic acid

 [0350] [Chemical 58]

1) 4- (5-Methyl-2-pyrazur) 2,4 Dioxobutanoic acid methyl ester 1- (5-Methyl-2-pyrazur) of Reference Example 8-2) 1 Ethanone (7.24 g) and dimethyl oxalate (12.6 g) And lithium bis (trimethylsilyl) amide (1.0M tetrahydrofuran solution, 58.5 ml) in the same manner as in Reference Example 8 3), 4 (5-methyl-2-pyrazuryl) 2,4 methyl dioxobutanoate Esters (7. 84g, 66%) as solids I got it.

 'H-NMR (400MHz, DMSO-d) δ: 2.63 (3H, s), 3.87 (3H, s), 7.41 (1

 6

 H, br s), 8.73 (1H, s), 9.13 (1H, s).

EI-MSm / z: 222 (M ⁺ ).

[0352] 2) 1— (6 Black-and-white 3 Pyridazil) 5— (5-Methyl 2-pyrazuryl) 1 1H-Pyrazole 3-carboxylic acid methyl ester

 4 (5-Methyl-2-pyrazurol) 2,4 Dioxobutanoic acid methyl ester (7.83 g) and 3 chloro-6-hydrazinopyridazine (5.09 g) were used in the same manner as 2) of Reference Example 4 (Method B). 1 (6 chloro-3 pyridazil) -5- (5-methyl-2-pyrazole) -1H-pyrazole-3-carboxylic acid methyl ester (6.60 g, 56%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.53 (3Η, s), 3.92 (3Η, s), 7.63 (1

 6

H, s), 8.20-8.29 (2H, m), 8.37 (1H, m), 8.99 (1H, d, J = l.5Hz) .EI-MSm / z: 330 (M ⁺ ).

 [0353] 3) Title compound

In an argon atmosphere, 1— ( ₆ — black mouth — ₃ — pyridazil) — ₅ — ( ₅ — methyl-2-biladyl) mono 1H pyrazole- 3-carboxylic acid methyl ester (6.58 g) in methanol (132 ml ) Sodium methoxide (3.22 g) was added to the suspension at room temperature, and the mixture was heated to reflux for 2 hours. After air cooling, water (132 ml) was added and stirred at room temperature for 1 hour. A 1N aqueous hydrochloric acid solution (50 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration to give the title compound (5.50 g, 89%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.51 (3Η, s), 4.05 (3Η, s), 7.48—

 6

 7.50 (2H, m), 8.04 (1H, d, J = 9.3Hz), 8.37 (1H, m), 8.91 (1H, d, J =

I.5Hz), 13.28 (1H, br s).

EI-MSm / z: 312 (M ⁺ ).

 [0354] [Reference Example 48] 1— (6-Methyl-3-pyridyl) -5- (5-Methyl-2-pyridyl) 1H Pyrazonole 3-Strong Norebonic acid

[0355] [Chemical 59]

[0356] 1) 1- (6-Methyl-3-pyridyl) -5- (5-Methyl-2-pyridyl) 1H Pyrazol lu 3-carboxylic acid ethyl ester

 Reference Example 15-3) 4-1- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (1.98 g) and Reference Example 7 5-hydrazino-1-ethylpyridine (1.04 g) in ethanol (40 ml) The solution was heated to reflux for 1 hour. Acetic acid (2.41 ml) was heated to reflux for 17 hours. Furthermore, concentrated hydrochloric acid (1.3 ml) was added to the reaction solution, and the mixture was heated to reflux for 1.5 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) 1 (6-methyl-3-pyridyl) -5- (5-methyl-2 pyridyl) —1H Pyrazole-3-carboxylic acid ethyl ester (0.887 g, 33%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.2Hz), 2.34 (3H, s), 2

 Three

 .59 (3H, s), 4.46 (2H, q, J = 7.2Hz), 7.20— 7.29 (3H, m), 7.49— 7.5 1 (1H, m), 7.73 (1H, dd, J = 8.3, 2.7 Hz), 8.33- 8.37 (2H, m).

 FAB— MSm / z: 323 (M + H +).

[0357] 2) Title compound

 1 (6-Methyl-3-pyridyl) -5- (5-Methyl-2-pyridyl) 1H Pyrazolu 3-Method similar to 4) in Reference Method 4 (Method B) using rubonic acid ethyl ester (0.882 g) Gave the title compound (0.752 g, 93%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.30 (3Η, s), 2.53 (3Η, s), 7.28 (1

 6

 H, s), 7.33 (1H, d, J = 8.3Hz), 7.58— 7.60 (1H, m), 7.65— 7.71 (2H, m), 8.28 (1H, m), 8.36 (1H, d, J = 2.7Hz), 13.08 (1H, br s).

FAB— MSm / z: 295 (M + H +). [0358] [Reference Example 49] 1— (6-Methoxy-3-pyridyl) 5— (1-Methyl 1H— 1, 2, 4 Triazole-3 yl) 1H Pyrazole-3—Strong rubonic acid ethyl ester

[0359] [Chemical 60]

[0360] 1) 4- (1-Methyl-5-phenylthio 1H-1,2,4-triazole 3-yl) 2,4-dioxobutanoic acid ethyl ester

Under an argon atmosphere, _3- acetyl-1-methyl- ₅ -phenolthio-iH-l, 2, 4-triazole (1.37 g, S. Ohta et al., Chem. Pharm. Bull., 1993, 41 (7), 122 6-1231 ), Cetyl oxalate (1.60 ml) and lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 7.05 ml) in the same manner as 3) of Reference Example 8, 4— (1— Methyl 5-phenolthio-1H—1,2,4triazole-3-yl) 2,4-dioxobutanoic acid ethyl ester (1.62 g, 82%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.38—1.43 (3Η, m), 3.93 (3Η, s), 4.3

 Three

 9 (2H, q, J = 7.2 Hz), 7. 25— 7. 46 (5H, m).

 ESI MSm / z: 334 (M + H) +.

[0361] 2) 1-(6 Methoxy 3 pyridyl) 5— (1 Methyl-5-phenylthio 1H— 1, 2, 4, 4 Triazole-3 yl) 1H Pyrazole 3—Strong rubonic acid ethyl ester 4— (1-Methyl) 5 Phenylthio- 1H— 1, 2, 4 Triazol-3 yl) 2, 4 Dioxobutanoic acid ethyl ester (439 mg) and 5 hydrazinone 2-methoxypyridine (183 mg) of Reference Example 2 in ethanol (30 ml) at room temperature 1M ethanol ethanol (1.98ml) was heated to reflux for 5 hours. After cooling with air, water and black form were separated into the reaction solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (ethyl acetate-hexane) to give 1- (6-methoxy-1-pyridyl) 5- (1-methyl-5 phenol). -Luthio 1H—1, 2, 4 G Riazole-3yl) 1H Pyrazole-3-strong rubonic acid ethyl ester (169 mg, 29%) was obtained as a solid.

ESI-MSm / z: 437 (M + H) ⁺ .

[0362] 3) Title compound

 1— (6-Methoxy-1-pyridyl) -5- (1-Methyl-5-phenolthiol 1H—1, 2, 4, 4 Triazole- 3 yl) 1H Pyrazole 3--Strong rubonic acid ethyl ester (1 65 mg) and Raney nickel (1 A suspension of Og, washed with ethanol and used in ethanol (20 ml) was heated to reflux for 2 hours. After cooling with air, the reaction solution was filtered, and Raney nickel (1.7 g, used after washing with ethanol) and ethanol (30 ml) and ethanol were added to the filtrate for 30 minutes under reflux. After air cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to give the title compound (68 mg, 55%) as a solid. Got as a body.

 ESI— MSm / z: 329 (M + H) +.

[0363] [Reference Example 50] 5- (5-Methoxyoxazole-2-yl) -1 (6-methyl-3-pyridyl) 1 1 H pyrazole 3 carboxylic acid

[0364] [Chemical 61]

1) N-Methoxycarboromethyloxamic acid methyl ester

 Using glycine methyl ester hydrochloride (12. 59 g), dimethyl oxalate (23. 65 g), triethylamine (14. Oml) and methanol (110 ml), E. Menta et al. (J. Heterocy clic Chem., 1995, 32, 1693) to give Ν-methoxycarboxylmethyloxamic acid methyl ester (19.86 g, quantitative) as an oil.

'H-NMR (400MHz, CDCl) δ: 3.79 (3Η, s), 3.92 (3Η, s), 4.14 (2H, d , J = 5.6Hz), 7.55 (1H, br).

ESI-MSm / z: 176 (M + H) ⁺ .

[0366] 2) 5-Methoxyoxazol-2-powered rubonic acid methyl ester

 Using N-methoxycarboxylmethyl oxamic acid methyl ester (19. 86 g), nitric pentoxide (72.4 g) and acetonitrile (300 ml), E. Menta et al. (J. Heterocyclic

Chem., 1995, 32, 1693), 5-methoxyoxazole-2-carbonic acid methyl ester (10. 26 g, 65%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.96 (3Η, s), 4.00 (3Η, s), 6.36 (1H, s)

 Three

ESI-MSm / z: 158 (M + H) ⁺ .

[0367] 3) 5-Methoxyoxazole-2-carboxylic acid

 Lithium hydroxide monohydrate at room temperature in a mixture of 5-methoxyoxazole-2-strong rubonic acid methyl ester (10. 26 g) in tetrahydrofuran (150 ml), methanol (75 ml) and water (75 ml) (3.072 g) was stirred for 2 hours. The reaction solution was made weakly acidic (PH4) by adding 1M hydrochloric acid-ethanol solution, and then most of the organic solvent was distilled off under reduced pressure. The resulting residue was subjected to liquid separation of black mouth form monomethanol (10: 1), the aqueous layer was extracted with black mouth form monoethanol (10: 1), and the combined organic layer was dried over anhydrous sodium sulfate. And dried. After separation by filtration, the solvent was distilled off under reduced pressure, and 5-methoxyoxazole-2-strong rubonic acid [1.06 g, 11%; ¾-NMR (400 MHz, DMSO d) δ: 3. 91 (3Η, s ), 6. 45 (1H, s). EI—

 6

MSm / z: 143 (M ⁺ )] was obtained as a solid. Further, the organic solvent in the aqueous layer was distilled off under reduced pressure, and the precipitated solid was collected by filtration and combined with the previously obtained solid to give a crude product of 5-methoxyoxazole-2-carboxylic acid (15. 63 g). Obtained.

[0368] 4) 5-Methoxyoxazole-2-Strong rubonic acid N-Methoxy-N-methylamide

To a mixed solution of 5-methoxyoxazole 2 carboxylic acid (15. 63 g) in dichloromethane (400 ml), acetonitrile (100 ml) and N, N dimethylformamide (100 ml), 1-hydroxybenzotriazole (9.69 g) at room temperature. , 3- (3 dimethylaminopropyl) 1-ethylcarbodiimide hydrochloride (27. 50 g), triethylamine (46 ml) and N, O-dimethylhydroxylamine hydrochloride (12. 79 g) were added and stirred for 19 hours. did. Reaction solvent Was distilled off under reduced pressure, and water (300 ml), 1-hydroxybenzotriazole (4.84 g), 3- (3 dimethylaminopropyl) 1 ethylcarbodiimide hydrochloride (8. 97 g), triethylamine (23 ml) and N, O dimethylhydroxylamine hydrochloride (6.98 g) were added and stirred for 3 days. Ethyl acetate was added to the reaction solution for separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone monochloroform). 5-Methoxyxazolruo 2-strong rubonic acid N-methoxy-N-methylamide (0. 89 g, 7.3%) as an oil.

 'H-NMR (400MHz, CDC1) δ: 3.46 (3Η, br), 3.85 (3Η, s), 3.98 (3H, s

 Three

 ), 6. 29 (1H, s).

ESI-MSm / z: 187 (M + H) ⁺ .

[0369] 5) 2-Acetyl-5-methoxyoxazole

 5-Methoxyoxazole- 2-strong rubonic acid N-methoxy-N-methylamide (0.89 g) and methyllithium (0.98 M in ethyl ether solution, 8.0 ml) In the same manner as described above, 2-acetyl-5-methoxyoxazole (0.258 g, 39%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.56 (3Η, s), 4.02 (3 (, s), 6.34 (1H, s)

 Three

EI-MSm / z: 141 (M ⁺ ).

[0370] 6) 4— (5-Methoxyoxazole-2-yl) 2, 4 Dioxobutanoic acid methyl ester

— Under cooling at 78 ° C, a solution of 2-acetyl-3-methoxyoxazole (0.258 g) and dimethyl oxalate (0.435 g) in tetrahydrofuran (12 ml) was added lithium bis (trimethylsilyl) amide (1.0 M Tetrahydrofuran solution (2.0 ml) was added dropwise, and the mixture was stirred for 20 minutes, and further stirred at 0 ° C for 1.5 hours. Water and jetyl ether were added to the reaction solution to separate it. The aqueous layer was made weakly acidic (pH 4) with a 1N aqueous hydrochloric acid solution, and extracted with black mouth form. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 4 (5-Methoxyoxazole-2-yl) 2,4 dioxobutanoic acid methyl ester (0.35) Og, 84%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.93 (3H, s), 4.07 (3H, s), 6.47 (1H, br

 Three

 s), 7.21 (1H, br s).

ESI— MSm / z: 228 (M + H) +.

7) 5- (5-Methoxyoxazole-2-yl) -1-(6-Methyl-3 pyridyl) -1H pyrazole 3-carboxylic acid methyl ester

 4 Methanol (15 ml) of 4- (5-methoxyoxazole-2-yl) 2,4 methyl dioxobutanoate (0.350 g) and 5-hydrazino mono-2-methylpyridine (0.219 g) of Reference Example 30 Heated to reflux for minutes. After air cooling, acetic acid (0.352 ml) was added to the reaction mixture, and the mixture was heated to reflux for 16 hours. After air cooling, the solvent of the reaction solution was distilled off under reduced pressure. A saturated aqueous sodium bicarbonate solution and black formaldehyde methanol (20: 1) were separated into the resulting residue, and the organic layer was saturated with brine. And then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 2-yl) 1- (6-methyl-3pyridyl) -1H pyrazole-3-carboxylic acid methyl ester (8 5.6 mg) was obtained as an oil. [ESI— MSm / z: 333 (M + H) +.]

 To a solution of methyl ester of 4,5 dihydro-5hydroxy-1H-pyrazole 3 carboxylic acid (85.6 mg) in dichloromethane (3.0 ml) at room temperature was added triethylamine (0.08 98 ml), methanesulfuric chloride (0.0399 ml) and 4- ( Dimethylamino) pyridine (4. lmg) was added and stirred for 1 hour. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (acetone monochloroform). 5-(5-Methoxyoxazole-2-yl) -1 ( 6-Methyl-3pyridyl) -1H pyrazole-3-strong rubonic acid methyl ester (25.2 mg, 5.2%) was obtained as a solid. 'H-NMR (400MHz, CDC1) δ: 2.65 (3Η, s), 3.89 (3Η, s), 3.97 (3H, s)

 Three

 , 6.12 (1H, s), 7.28 (1H, d, J = 8.3Hz), 7.37 (1H, s), 7.78 (1H, dd, J = 8.3, 2.4Hz), 8.63 (1H, d, J = 2.4 Hz).

FAB— MSm / z: 315 (M + H) +. [0372] 8) Title compound

 5- (5-Methoxyoxazol-2-yl) -1- (6-methyl-3-pyridyl) -1H-pyrazole-3-methyl rubonic acid methyl ester (25.2 mg) and lithium hydroxide monohydrate ( In the same manner as in Reference Example 31, 5), the title compound (14.9 mg, 62%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.56 (3Η, s), 3.87 (3Η, s), 6.41 (1

 6

 H, s), 7. 27 (1H, s), 7. 42 (1H, d, J = 8.3 Hz), 7. 90 (1H, dd, J = 8. 3, 2.

7Hz), 8.59 (1H, d, J = 2.7Hz).

 FAB MSm / z: 301 (M + H) +.

[0373] [Reference Example 51] 1— (6-Methoxy-3-pyridyl) -5- (2-methyl-1H-imidazole)

 4Hil) 1H Pyrazole-3—Strong rubonic acid ethyl ester

[0374] [Chemical 62]

[0375] 1) 1 {2—Methyl-1 [(4 Methylphenol) sulfol] 1H-imidazole 4 —yl} — 1-ethanone

1- (2-Methyl 1H-imidazole-4-yl) 1-ethanone (1.00 g, LA Re iter, J. Org. Chem., 1987, 52, 2714-2726) in dichloromethane (20 ml) at room temperature And triethylamine (1.67 ml) and 4-methylbenzenesulfuryl chloride (1.83 g) were added and stirred for 1.5 days. Ethyl acetate and water were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform). 1-{2-Methyl-1 [(4-methylphenol) sulfol] 1H-imidazole-4-yl} -1 ethanone (2.l lg, 94%) was obtained as an oil. H—NMR (400MHz, CDC1) δ: 2. 47 (3Η , s), 2.49 (3H, s), 2.54 (3H, s), 7.40 (2H, d, J = 8.3Hz), 7.82 (2H, d, J = 8.3Hz), 8.02 (1H, s).

 ESI— MSm / z: 279 (M + H) +.

[0376] 2) Title compound

 — Under cooling at 78 ° C, 1 {2-methyl-1 [(4 methylphenol) sulfol] 1H-imidazole-4-yl}-1-ethanone (1.97 g) in tetrahydrofuran (7 ml) solution with lithium bis (Trimethylsilyl) amide (1.OM in tetrahydrofuran, 7.78 ml) was added and stirred for 35 minutes. After dropwise addition of decyl oxalate (1.44 ml) to the reaction solution, the mixture was gradually warmed to room temperature and stirred for 4.5 hours. To this reaction solution, an ethanol (35 ml) solution of 5 hydrazinone 2-methoxypyridine (0.771 g) of Reference Example 2 and a 1M hydrochloric acid ethanol solution (7.78 ml) were heated and refluxed for 13 hours. After air cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (0.353 g, 15%) as amorphous.

 'H-NMR (400MHz, CDC1) δ: 1.40 (3Η, t, J = 7.1Hz), 2.39 (3H, s), 3

 Three

 .97 (3H, s), 4.42 (2H, q, J = 7.1Hz), 6.44 (1H, s), 6.80 (1H, d, J = 8.8 Hz), 7.19 (1H, br s), 7.68 (1H , dd, J = 8.8, 2.7Hz), 8.24 (1H, d, J = 2.7Hz).

 ESI— MSm / z: 328 (M + H) +.

[0377] [Reference Example 52] 5— (3—Strengthening ruber moile 1H—Pyro 1 lu 1) 1 (6-Methoxy

 3 pyridyl) -1H-pyrazole 3 carboxylic acid ethyl ester

[0378] [Chemical 63]

[0379] 1)5- (3—カルボキシ— 1H ピロール— 1—ィル）—1— (6—メトキシ— 3 ピリジ ル） 1 H ピラゾール 3 カルボン酸ェチルエステル

[0379] 1) 5- (3-Carboxy-1H pyrrole-1-yl) -1-1- (6-Methoxy-3 pyridyl) 1 H pyrazole 3 carboxylic acid ethyl ester

 Under cooling at 0 ° C, Reference Example 38 5— (3 Formyl 1H Pyroluene 1 Fil) 1 1 (6 —Methoxy-3-pyridyl) -1H Pyrazole-3-carboxylic acid ethyl ester (0.6 80 g) and Amidosulfuric acid (0.583) Sodium chlorite (0.543 g) was added to a mixed solution of g) of dioxane (10 ml), acetonitrile (20 ml) and water (10 ml), and the mixture was gradually warmed to room temperature and stirred for 21.5 hours. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the resulting residue for separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting solid was capped with jetyl ether, and the precipitated solid was collected by filtration. 5- (3-Carboxy-1H-pyrrole-1-yl) -1— (6-Methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (0.191 g, 26%) was obtained.

 'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.1Hz), 3.95 (3H, s), 4

 Three

 .46 (2H, q, J = 7.2Hz), 6.63— 6.64 (1H, m), 6.73— 6.74 (1H, m), 6.7 6 (1H, d, J = 9.0Hz), 7.00 (1H, s) , 7.37- 7.38 (1H, m), 7.48 (1H, dd, J = 8.9, 2.7Hz), 8.02 (1H, d, J = 2.7Hz).

ESI-MSm / z: 357 (M + H) ⁺ .

[0380] 2) Title compound

 5- (3-Carboxy-1H pyrrole-1-yl) -1- (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (0.19 lg) and ammonium chloride (0.143 g) In the same manner as in Reference Example 8 1), the title compound (0.123 g, 64%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.1Hz), 3.94 (3H, s), 4

 Three

 .46 (2H, q, J = 7.1Hz), 5.50 (2H, br

 s), 6.51 (1H, dd, J = 2.9, 1.7Hz), 6.64 (1H, dd, J = 2.9, 2.2Hz), 6.7 5 (1H, d, J = 9.3Hz), 6.98 (1H, s) , 7.26- 7.27 (1H, m), 7.47 (1H, dd, J = 8.9, 2.8Hz), 8.01 (1H, d, J = 2.4Hz).

 ESI— MSm / z: 356 (M + H) +.

[0381] [Reference Example 53] 5- (5-tert-butoxycarbolamino 2 pyrajur) -1 (6-medium Toxi-3-pyridazil) 1H Pyrazole 3-carboxylic acid

[0382] [Chemical 64]

[0383] 1) 1— (6-Methoxy-1-pyridazil) 5-— (5-Methyl-2-pyrazur) -1-H-pyrazole 3-carboxylic acid methyl ester

 Argon atmosphere Under cooling at 0 ° C, Reference Example 47 1 (6-Methoxy-3 pyridazil) -5- (5-Methyl-2 pyrajuryl) — 1H Pyrazole-3-carboxylic acid (3.50 g) in dichloromethane ( (Trimethylsilyl) diazomethane (2.OM in hexane, 6.72 ml) was added dropwise to a mixed suspension of 70 ml) and methanol (35 ml) and stirred for 1.5 hours. Further, (trimethylsilyl) diazomethane (2.OM in hexane, 6.72 ml) was added dropwise to the reaction solution and stirred for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform). 1- (6-Methoxy-3-pyridazil) -5- (5- Methyl-2-pyrazurol) 1H-Pyrazole-3-methyl ruvic acid methyl ester (3.41 g, 93%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.59 (3Η, s), 4.00 (3Η, s), 4.11 (3H, s)

 Three

 , 7. 18 (1H, d, J = 9.3 Hz), 7. 27— 7. 29 (1H, m), 7. 98— 8.01 (1H, m), 8. 29 (1H, m) , 8. 71 (1H, d, J = l. 5Hz).

 EI— MSmZz: 326 (M +).

[0384] 2) 5-(5-Carboxy-2-pyriduryl)-1- (6-Methoxy-3 pyridazil)-1 H pyrazole 3-carboxylic acid methyl ester

1- (6-Methoxy-1-pyridazil) 5- (5-Methyl-2-pyrazyl) 1H Pyrazole-3-carboxylic acid methyl ester (3.40 g), selenium dioxide (4.62 g) 5— (5 Carboxy-2 pyrajur) -1 (6 —Methoxy-3-pyridazil) 1H-pyrazole-3-carboxylic acid methyl ester (2.57 g, 69%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.92 (3Η, s), 4.05 (3Η, s), 7.52 (1

 6

 Η, d, J = 9.3Hz), 7.77 (1H, s), 8.10 (1H, d, J = 9.3Hz), 8.98 (1H, d, J = 1.5Hz), 9.21 (1H, d, J = l .5Hz)

 EI— MSmZz: 356 (M +).

[0385] 3) 5- (5-tert-Butoxycarbo-lamino 2-pyramid) 1 1- (6-Methoxy 1 3

 1-pyrazole 3 carboxylic acid methyl ester

 5- (5-Carboxy-2-pyriduryl)-1- (6-Methoxy-3-pyridazil)-1 H pyrazole-3-carboxylic acid (2.56 g), diphenylphosphoryl azide (1.70 ml) and tert-butanol ( 5— (5-tert-butoxycarbo-laminomino-2-pyrazuryl) -1- (6-methoxy-1-tripyridadiyl) — 1H Pyrazole-3-carboxylic acid methyl ester (0.886 g, 29%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.54 (9Η, s), 4.00 (3Η, s), 4.12 (3H, s)

 Three

 , 7.17 (1H, d, J = 9.3Hz), 7.24— 7.27 (1H, m), 7.57 (1H, s), 7.95 (1H, d, J = 9.3Hz), 8.48 (1H, d, J = l .5Hz), 9.11 (1H, d, J = l.5Hz).

EI-MSm / z: 427 (M ⁺ ).

[0386] 4) Title compound

 5- (5-tert-Butoxycarbolamino-2-pyridur) -1- 1- (6-Methoxy-1-3-pyridazil)-1H pyrazole-3-carboxylic acid methyl ester (0.880 g) tetrahydrofuran (18 ml) A 1N aqueous sodium hydroxide solution (5.15 ml) was stirred for 4 hours at room temperature in a mixed suspension of methanol and methanol (18 ml). The reaction mixture was neutralized with 1N aqueous hydrochloric acid (5.15 ml), water (250 ml) was further added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound (0.732 g, 86%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.48 (9Η, s), 4.05 (3Η, m), 7.44 (

 6

1H, m), 7.49 (1H, dd, J = 9.3, 1.0Hz), 8.02 (1H, dd, J = 9.3, 1.0Hz), 8.71 (1H, m), 8.82 (1H, m), 10.39 (1H , s). EI-MSm / z: 413 (M +).

[0387] [Reference Example 54] (2R) 2 Fluoromethylpyrrolidine hydrochloride

[0388] [Chemical 65]

[0389] 1) (2R) —N Benzyloxycarbonyl— 2 Hydroxymethylpyrrolidine

 Borane dimethylsulfide (3.23 ml) was added to a tetrahydrofuran (50 ml) solution of N-benzyloxycarbolulu D-proline (4.02 g) at room temperature, and the mixture was heated to reflux for 2 hours. Under ice-cooling, 1N aqueous hydrochloric acid solution was added to the reaction solution, treated with excess borane dimethylsulfide, and then liquid was added to form liquid. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane acetate), and (2R) -N benzyloxycarbonyl-2-hydroxymethylpyrrolidine ( 3. 68 g, 97%) were obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 57— 2. 05 (4Η, m), 3. 36— 3. 68 (4Η,

 Three

 m), 4.01 (1H, br s), 4.39 (1H, br s), 5. 15 (2H, s), 7. 32 (5H, m). ESI— MSm / z: 236 (M + H) +.

[0390] 2) (2R) —N Benzyloxycarboxyl 2— (p-Toluenesulfo-oxymethyl) pyrrolidine

 To a solution of (2R) -N benzyloxycarbonyl-2 hydroxymethylpyrrolidine (3.62 g) in pyridine (70 ml) was added p-toluenesulfuryl chloride (3.52 g) at room temperature, and the mixture was stirred overnight. Water and jetyl ether were added to the reaction liquid and the phases were separated, and the organic layer was washed with 1N aqueous hydrochloric acid and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane), and (2 R) —N benzyloxycarboxyl 2- (p toluenesulfo -Luxoxymethyl) pi-lysine (1.82 g, 30%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 81— 2. 40 (4Η, m), 2. 42 (3Η, br s),

 Three

3. 37 (2H, s), 3. 90-4. 20 (3H, m), 4. 96— 5. 10 (2H, m), 7. 26— 7. 78 ( 9H, m).

 [0391] 3) (2R) —N Benzyloxy-Carlo 2 Fluoropyrrolidine

 (2R) —N benzyloxycarboru 2— (p toluenesulfo-oxymethyl) pyrrolidine (1.82 g) and tetrabutylammonium fluoride trihydrate (2.95 g) in acetonitrile (50 ml) The mixture was stirred overnight at an external temperature of 75 ° C. After air cooling, water and ethyl acetate were added to the reaction solution and the phases were separated. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane), and (2R) -N benzyloxycarboxyl 2-fluoropyrrolidine (705 mg, 64 %) Was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1. 87— 2. 04 (4Η, m), 3. 46 (2Η, s), 4.0

 Three

 3-4. 61 (3H, m), 5. 14 (2H, dd, J = 19. 8, 12. 5Hz), 7. 31— 7. 37 (5H, m).

 [0392] 4) Title compound

 At room temperature, a suspension of (2R) -N benzyloxycarboru 2 fluoropyrrolidine (699 mg), 10% palladium on carbon (300 mg) and concentrated hydrochloric acid (lml) in methanol (30 ml) was stirred overnight under a hydrogen atmosphere. did. The reaction suspension was filtered off, and the filtrate solvent was evaporated under reduced pressure and solidified from methanol-jetyl ether to give the title compound (358 mg, 87%) as a solid.

 'H-NMR (400MHz, DMSO- d) δ: 1. 58—3.22 (6Η, m), 3.76—3.80 (

 6

 1Η, m), 4. 55-4.70 (2H, m), 9.58 (2H, br s).

[0393] [Reference Example 55] 1— (6-Methoxypyridazine-3 yl) -5- (1-Methyl-1H-pyrrole-3 yl) -1H-pyrazole 3 carboxylic acid

[0394] [Chemical 66]

1) 1— (6 クロ口ピリダジン一 3—ィル） 5— (1—メチル 1H ピロール一 3—ィ ル） 1 H ピラゾール 3 カルボン酸メチルエステル

1) 1— (6 Chloropyridazine 1-yl) 5— (1-Methyl 1H pyrrole 3-yl) 1 H Pyrazole 3 Carboxylic acid methyl ester

 — Under cooling at 78 ° C, add lithium bis (trimethylsilyl) amide (1. OM in tetrahydrofuran, 27.8 ml) to a solution of 3-acetyl-1-methyl-1H pyrrole (3. OOml) in tetrahydrofuran (30 ml). And stirred for 45 minutes. A solution of dimethyl oxalate (4.48 g) in tetrahydrofuran (15 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. To the reaction solution, 3-chlorodihydric hydrazinopyridazine (4.40 g), concentrated hydrochloric acid (2.08 ml), and methanol (150 ml) were added, and the mixture was heated to reflux for 16 hours. Further, concentrated hydrochloric acid (1.04 ml) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. After air cooling, saturated sodium bicarbonate aqueous solution, water, and ethyl acetate were added to the residue obtained by evaporating the solvent of the reaction solution under reduced pressure, and the precipitated solid was collected by filtration to give 1- (6 black-open pyridazine— 3-yl) -5- (1-methyl-1H pyrrole-3-yl) -1Η pyrazole-3-carboxylic acid methyl ester (2.83 g, 35%) was obtained.

'H-NMR (400MHz, DMSO-d) δ: 3.57 (3Η, s), 3.85 (3Η, s), 5.94 (1

 6

 Η, t, J = l.9Hz), 6.69 (1H, t, J = l.9Hz), 6.89 (1H, br), 7.00 (1H, s), 8. 10 (1H, d, J = 8.0Hz ), 8.20 (1H, d, J = 8.0Hz).

EI-MSm / z: 317 (M ⁺ ) for ³⁵ C1.

2) Title compound

 1- (6 Chloropyridazine-3-yl) -5- (1-Methyl 1H pyrrole-3-yl) -1H Pyrazole-3-carboxylic acid methyl ester (2.80 g) in methanol (50 ml) and tetrahydrofuran Sodium methoxide (1.43 g) was added to a suspension of (50 ml) at room temperature, and the mixture was heated to reflux for 4 hours. After air cooling, 1M aqueous sodium hydroxide solution (18.0 ml) was added, and the mixture was stirred overnight. The solvent in the reaction solution was distilled off under reduced pressure, water and jetyl ether were added to the resulting residue, and the resulting precipitate was filtered off. A 1M aqueous hydrochloric acid solution was added to the solvent of the filtrate, and the precipitated solid was collected by filtration to obtain the title compound (1.02 g, 39%).

'H-NMR (400MHz, DMSO-d) δ: 3.55 (3Η, s), 4.11 (3Η, s), 5.82—

 6

 5.86 (1H, m), 6.67 (1H, t, J = 2.4Hz), 6.76 (1H, t, J = 2.4Hz), 6.88 (1 H, s), 7.50 (1H, d, J = 9.1Hz) , 7.84 (1H, d, J = 9.1Hz).

EI— MSmZz: 299 (M +). [Reference Example 56] 1-Ethylu-2-oxopiperazine hydrochloride

[0396] [Chemical 67]

0

_/ ^ ^ -HCI

 HN Ν- \ ^ f \

[0397] 1) 3-oxopiperazine 1 Tributylamine (7 ml) mixed with tetrahydrofuran (50 ml) and methanol (50 ml) of tert-butyl ester piperazine 2-one (5.07 g) at room temperature. 76 ml) and di tert butyl dicarbonate (12. 17 g) were added and stirred for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue obtained was added with jetyl ether, and the precipitated solid was collected by filtration to give 3-oxopiperazine-1-carboxylic acid tert-butyl ester (9. 36 g, 92%).

 'H-NMR (400MHz, DMSO-d) δ: 1.40 (9Η, s), 3.15 (2 (, br), 3.45

 6

 (2H, br), 3.81 (2H, br), 8.03 (1H, br).

ESI-MSm / z: 201 (M + H) ⁺ .

[0398] 2) 4-Ethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

 To the above solution of 3-oxopiperazine (1) tert-butyl ester of rubonic acid (9.36 g) in N, N-dimethylformamide (105 ml), add sodium hydride (1.361 g) at 0 ° C for 25 minutes. Stir. To the reaction solution was added iodide chill (4.48 ml), and the mixture was stirred at 40 ° C for 15 hours. Cold water and ethyl acetate were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-acetone) to give 4-ethyl-3-oxopiperazine-1-carboxylic acid te rt-butyl ester ( 8. 69 g, 81%) was obtained as a pale yellow transparent oil.

 'H-NMR (400MHz, CDC1) δ: 1.15 (3Η, t, J = 7.1 Hz), 1.46 (9H, s), 3

 Three

 33 (2H, t, J = 5.4Hz), 3.46 (2H, q, J = 7.1Hz), 3.64 (2H, t, J = 5.4Hz), 4.06 (2H, s).

EI-MSm / z: 228 (M +). [0399] 3) Title compound

 To a solution of the above 4-ethyl 3-oxopiperazine 1 carboxylic acid tert-butyl ester (8.69 g) in dichloromethane (170 ml) was added 4M hydrochloric acid dioxane solution (60 ml) at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (5.88 g, 94%) as an oil.

 'H-NMR (400MHz, DMSO-d) δ: 1. 04 (3Η, t, J = 7.1 Hz), 3. 29— 3.3

 6

 9 (4H, m), 3.53 (2H, t like, J = 5.6Hz), 3.63 (2H, br), 10.00 (2H, br)

FAB MSm / z: 129 (M + H) +.

[0400] [Reference Example 57] 1— (6-Methoxypyridazine—3 yl) -5— (1H—Pyroleuro 3-yl

) — 1H pyrazole 3 carboxylic acid

[0401] [Chemical 68]

[0402] 1) 2, 4 Dioxo 4- (1-Felsulfol-Lu 1H pyrrole 3-yl) butanoic acid methyl ester

Under cooling at 78 ° C, a solution of 3 acetyl-1-phenolsulfurol 1H pyrrole (2.23 g) in tetrahydrofuran (10 ml) was added to lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 9.85 ml). And stirred for 45 minutes. To the reaction solution was added a solution of dimethyl oxalate (1.60 g) in tetrahydrofuran (5. Oml), and the mixture was stirred at room temperature for 22 hours. The solvent of the reaction solution was distilled off under reduced pressure, and water, 1M aqueous hydrochloric acid solution, and ethyl acetate were added to the residue to separate the solution. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 2,4 Dioxo-4- (1-phenylsulfo-lulu 1H pyrrole-3-yl) butanoic acid methyl ester (1.76 g, 59% ) Was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.83 (3Η, s), 6.82 (1Η, br), 7.00 (

 6

 1Η, br), 7.52 (1H, br), 7.69 (2H, t, J = 7.6Hz), 7.80 (1H, t, J = 7.6Hz

), 8.11 (2H, d, J = 7.6Hz), 8.63 (1H, br).

 ESI— MSm / z: 336 (M + H) +.

 [0403] 2) 1— (6 Chloropyridazine 1-yl) 5— (1-Phenolsulfol 1 H Pyro 1 Lu 3 yl)-1H Pyrazole 3-Carboxylic acid methyl ester

 In a solution of 2,4 dioxo-4- (1-phenolsulfurol 1H pyrrole-3-yl) butanoic acid methyl ester (1.76 g) in methanol (30 ml) at room temperature, 3 Dinopyridazine (0.759 g) was added and heated to reflux overnight. After air cooling, concentrated hydrochloric acid (1. Oml) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. After cooling with air, the solvent of the reaction solution was distilled off under reduced pressure.

. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane-jetyl ether) to give 1— ( ₆ —clopyridazine- ₃ —yl) —5— (1 —Fuelsulfo-Lu 1H pyrrole— 3—yl) —1H pyrazole

—3—Carboxylic acid methyl ester and 1— (6-methoxypyridazine 1-yl) 5— (1-phenylsulfol 1H pyrrole 3 yl) 1H pyrazole 3 Carboxylic acid methyl ester mixture (1.85 g The ratio 8: 1) was obtained as an amorphous material.

 'H-NMR (400MHz, CDC1) δ: 3.96 (3Η, s), 6.38—6.41 (1Η, m), 7.0

 Three

 0 (1H, s), 7. 12-7.17 (1H, m), 7.50— 7.71 (5H, m), 7.90 (2H, d, J = 7.3Hz), 8.03 (1H, d, J = 9.0Hz ).

 ESI-MSm / z: 444 (M + H) +.

[0404] 3) Title compound

Above 1— (6 Pyridazine-3—yl) —5— (1-Felsulfol--1H pyrrole-3-yl) —1H Pyrazole-3-carboxylic acid methyl ester and 1- (6— Methoxypyridazine— 3—yl) —5— (1—phenolsulfol— 1H pyrrole— 3— 1) Sodium methoxide (0.676 g) was added at room temperature to a mixture of methanol (30 ml) and tetrahydrofuran (50 ml) in a mixture containing 1.H-pyrazole-3-methyl rubonic acid methyl ester (1.85 g) and stirred for 4 hours. did. To the reaction solution, 1M aqueous sodium hydroxide solution (9. Om 1) was added and stirred overnight. The reaction mixture was neutralized with 1M aqueous hydrochloric acid, and the solvent in the reaction mixture was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound (1.20 g, 80% in 2 steps).

'H-NMR (400MHz, DMSO-d) δ: 4.43 (3Η, s), 6.22 (1Η, t, J = l.7H

 6

 z), 7.01-7.07 (1H, m), 7.09— 7.15 (1H, m), 7.25 (1H, s), 7.81 (1H

, d, J = 9.2Hz), 8.18 (1H, d, J = 9.2Hz), 11.38 (1H, br).

 FAB MSm / z: 286 (M + H) +.

[0405] [Reference Example 58] 5— (1-ethylyl 1H—pyrrole 3-yl) 1 (6 methylpyridine

 3 Hil) 1H Pyrazole-3-Power rubonic acid

[0406] [Chemical 69]

[0407] 1) 2, 4 Dixo 1- (1-Phenolsulfo-Lu 1H Pyrrole 3-3-yl) butanoic acid ethyl ester

While cooling at 78 ° C, add lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 46.3 ml) to tetrahydrofuran (40 ml) solution of 3 acetyl-1-phenolsulfurol 1H pyrrole (10.7 g). Stir for 45 minutes. To the reaction solution, ethyl oxalate (8.60 ml) was added, followed by stirring at room temperature for 22 hours. The solvent of the reaction solution was distilled off under reduced pressure, and water, 1M aqueous hydrochloric acid solution and ethyl acetate were added to the residue to separate the solution. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 2, 4 Dixosone 4 (1 phenolsulfurol 1H pyrrole) 3yl) butanoic acid ethyl ester (12.4 g, 84%) was obtained as a solid.

 ESI— MSm / z: 350 (M + H) +.

[0408] 2) 1— (6 Methylpyridine 3 yl)-5- (1—Phenolsulfol— 1H Pyroluene 3 yl) 1H Pyrazole 3-Strong rubonic acid ethyl ester

 2,4 Dioxo-4- (1-phenolsulfurol 1H pyrrole-3-yl) butanoic acid ethyl ester (1.525 g) and 5 hydrazino 2-methylpyridine of Reference Example 7 (67 8 mg) in ethanol (67 8 mg) The solution was heated to reflux for 30 minutes. After air cooling, concentrated hydrochloric acid (0.00674 ml) was added to the reaction solution, and the mixture was heated to reflux for 20 hours. After air cooling, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and black mouth form were separated into the resulting residue. Further, the aqueous layer was extracted with chloroform, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black mouth form-acetone) and purified 1- (6-methylpyridine-3-yl) —5— (1 —Phenolsulfo-Lu 1H pyrrole-3-yl) —1H Pyrazole-3 The olbonic acid ethyl ester (0.96 g, 50%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.40 (3Η, t, J = 7.1 Hz), 2.64 (3H, s), 4

 Three

 43 (2H, q, J = 7.1 Hz), 6. 05— 6. 08 (1H, m), 6. 94— 7.00 (2H, m), 7. 0 8- 7. 13 (1H , m), 7. 21 (1H, d, J = 8.8Hz), 7. 51— 7. 70 (4H, m), 7. 78-7. 82 (2H, m), 8. 46 (1H , d, J = 2.7 Hz).

 FAB MSm / z: 437 (M + H) +.

[0409] 3) 1— (6-Methylpyridine-3-yl)-5- (1H pyrrole-3-yl) 1H-virazole 3-carboxylic acid

 1- (6-Methyl-3 pyridyl)-5- (1-phenylsulfolulu 1H pyrolulu 3-yl) -1H-pyrazole 3-carboxylic acid ethyl ester (0.96 g) in ethanol (15 ml) The solution was added with 1M aqueous sodium hydroxide solution (15 ml) at room temperature and stirred for 16 hours. The reaction solution was neutralized with 1M aqueous hydrochloric acid, and the solvent of the reaction solution was distilled off under reduced pressure. The precipitated solid was collected by filtration. 1— (6-Methylpyridine-3-yl) —5— (1H pyrrole— 3 —yl) — 1H Pyrazole-3-carboxylic acid (0.487 g, 83%) was obtained.

'H-NMR (400MHz, DMSO-d) δ: 2. 56 (3Η, s), 5. 83— 5. 86 (1Η, m) , 6. 67-6. 75 (2H, m), 6. 89 (1H, s), 7. 42 (1H, d, J = 8.3Hz), 7. 77 (1H, dd, J = 2. 7, 8. 3Hz), 8. 47 (1H, d, J = 2.7Hz), 11. 06 (1H, br).

 FAB MSm / z: 269 (M + H) +.

[0410] 4) 1- (6-methylpyridine 1-yl) -5- (1H-pyrrole 3-yl) 1- 1H-virazole 3-carboxylic acid ethyl ester

 1- (6-Methylpyridine-3-yl) -5- (1-phenolsulfurol 1H-pyrrole-3 yl) 1H pyrazole 3-strength rubonic acid ethyl ester (0.955 g) in ethanol (20 ml) ) A 20% sodium ethoxide-ethanol solution (2.88 g) was added to the solution at room temperature and stirred for 1 hour. Under cooling at 0 ° C, 1M hydrochloric acid-ethanol solution was added to the reaction solution, and the solvent of the reaction solution was distilled off under reduced pressure. To the resulting residue, black mouth form and saturated aqueous sodium hydrogen carbonate solution were separated. did. Further, the aqueous layer was extracted with black mouth form, and the combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formaldehyde). 1— (6-Methylpyridine-3-yl) —5— (1H Pyrrole-3-yl) 1H-Pyrazol-3-strong rubonic acid ethyl ester (0.26 g, 40%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41 (3Η, t, J = 7.1 Hz), 2.62 (3H, s), 4

 Three

 44 (2H, q, J = 7.1 Hz), 6. 00— 6. 05 (1H, m), 6. 56— 6. 62 (1H, m), 6. 7 0-6. 75 (1H , m), 6. 95 (1H, s), 7. 22 (1H, d, J = 8.3 Hz), 7. 70 (1H, dd, J = 2. 7, 8. 3 Hz), 8. 35 (1H, br), 8. 56 (1H, d, J = 2.7 Hz).

 FAB MSm / z: 297 (M + H) +.

[0411] 5) 5-(1-Ethyl-1H pyrrole-3-yl) -1- (6-methylpyridine-3-yl) 1H pyrazole 3 carboxylic acid ethyl ester

N, N dimethylformamide (7.0 ml) of 1-11 (6 methylpyridine 3 yl) -5- (1H-pyrrole 3 yl) 1H-pyrazole-3-carboxylic acid ethyl ester (0.254 g) To the solution were added hydrogen sodium (60%, 43.9 mg) and Xuwechinoren (0.0 824 ml) at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride and ethyl acetate was added for liquid separation. In addition, the aqueous layer was extracted with ethyl acetate and combined. The machine layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform-acetone) to give 5- (1-ethyl-1H pyrrole-3-yl) -1— (6-Methylpyridine-3-yl) -1H pyrazole-3-carboxylic acid ethyl ester (0.277 g, 99%) was obtained as an oily product.

 'H-NMR (400MHz, CDC1) δ: 1.37 (3Η, t, J = 7.3Hz), 1.41 (3H, t, J =

 Three

 7.1Hz), 2.62 (3H, s), 3.85 (2H, q, J = 7.3Hz), 4.43 (2H, q, J = 7.1Hz), 5.85-5.89 (1H, m), 6.49 (1H, t , J = 2.0Hz), 6.55 (1H, t, J = 2.0Hz), 6.91 (1H, s), 7.23 (1H, d, J = 8.3Hz), 7.71 (1H, dd, J = 2.4, 8.3Hz ), 8.57 (1H, d, J = 2.4Hz).

 FAB MSm / z: 325 (M + H) +.

[0412] 6) Title compound

 5- (1-Ethyl-1H pyrrole-3-yl) -1- (6-Methylpyridine-3-yl) 1H Pyrazole 3-Strong rubonic acid ethyl ester (0.277 g) with methanol (3. Oml) Lithium hydroxide monohydrate (40. lmg) was added to a mixed solution of water (1.8ml) at room temperature and stirred for 2 hours. The solvent of the reaction solution was evaporated under reduced pressure, 1M aqueous hydrochloric acid solution was added to the resulting residue, and the precipitated solid was collected by filtration to obtain the title compound (0.193 g, 76%).

 'H-NMR (400MHz, DMSO-d) δ: 1.19 (3Η, t, J = 7.3Hz), 2.49 (3H,

 6

 s), 3.77 (2H, q, J = 7.3Hz), 5.63- 5.66 (1H, m), 6.68 (1H, t like, J =

2.7Hz), 6.75 (1H, t like, J = 2.2Hz), 6.79 (1H, s), 7.34 (1H, d, J = 8.

3Hz), 7.70 (1H, dd, J = 2.7, 8.3Hz), 8.40 (1H, d like, J = 2.7Hz).

FAB MSm / z: 297 (M + H) +.

[0413] [Reference Example 59] 5- (5 cyanopyridine-2-yl) -1 (6-methoxypyridazine 1-yl) 1 1 H pyrazole 3 carboxylic acid

[0414] [Chemical 70]

[0415] 1) 2 Acetenolay 5 Xianopyridine

 3 A mixture of cyanopyridine (3.12 g), pyruvic acid (6.23 ml) and silver nitrate (1.27 g) in dichloromethane (150 ml) and water (150 ml) at room temperature with ammonium peroxodisulfate (10. 3g) was added slowly. Under ice-cooling, sulfuric acid (3.2 ml) was gradually added to the reaction solution, followed by stirring at 40 ° C for 1.5 hours. Under ice-cooling, the reaction mixture was made alkaline with 1M aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to obtain 2-acetyl-5-cyanopyridine (903 mg, 21%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.75 (3Η, s), 8. 13— 8. 16 (2Η, m), 8.9

 Three

 5 (1H, d, J = l. 2Hz).

 [0416] 2) 4- (5 Cyanpyridine-2-yl) 2, 4 Dioxobutanoic acid methyl ester

 Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 38.4 ml) was added to an anhydrous tetrahydrofuran (250 ml) solution of 2 acetyl-5-cianopyridine (5.10 g) under an argon atmosphere and cooling at -78 ° C. And stirred for 35 minutes. To the reaction solution, a solution of dimethyl oxalate (6.18 g) in tetrahydrofuran (100 ml) was stirred for 5 minutes, and then stirred at room temperature for 75 minutes. Ice and 1M aqueous hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. The residue obtained by removing hexane was collected by filtration. 4-1- (5-Cyanopyridin-2-yl) 2,4 Dioxobutanoic acid methyl ester ( 5. 325 g, 66%) was obtained. ESI— MSm / z: 233 (M + H) +.

[0417] 3) 1— (6 3-Dye pyridazine 3-yl) 5— (5 2-Sianopyridine 2-yl) 1H Pyrazole carboxylic acid methyl ester

 A methanol (100 ml) solution of the above 41 (5-cyanopridin-2-yl) -2,4 dioxobutanoic acid methyl ester (2.32 g) and 3 black hydrazinopyridazine (1.44 g) was heated to reflux overnight. Acetic acid (2 ml) was added to the reaction solution, and the mixture was heated to reflux for 2 hours. Further, concentrated hydrochloric acid (lml) was added to the reaction solution, and the mixture was heated to reflux for 1.5 hours. After air cooling, the precipitated solid was filtered off, and the resulting solid was purified by silica gel column chromatography (black mouth form-methanol). 1— (6 black mouth pyridazine—3—yl) —5— (5 cyanopyridine — 2-yl) 1H Pyrazole-carboxylic acid methyl ester (2.94 g, 86%) was obtained as a solid. 'H-NMR (400MHz, CDC1) δ: 4.01 (3Η, s), 7.32 (1Η, s), 7.73—7.77

 Three

 (2Η, m), 8.07 (1H, dd, J = 8.2, 2.1 Hz), 8.14 (1H, d, J = 9. OHz), 8.66 8.67 (1H, m).

ESI-MSm / z: 341 (M + H) ⁺ .

[0418] 4) 5- (5 Cyanpyridine 1-yl) 1- (6-Methoxypyridazine 1-yl) 1H Pyrazole 3-Carboxylic acid methyl ester

In an argon atmosphere, the above 1 1 ( ₆ 1-cylpyridazine 1 ₃ yl) 1 ₅ 1 ( ₅ 1 cyanopyridin 2 yl) 1H pyrazole-carboxylic acid methyl ester (1.19 g) and sodium methoxide (189 mg) In methanol (70 ml) was heated to reflux for 20 minutes. To the reaction solution, a 1M aqueous hydrochloric acid solution and black mouth form were added for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane acetone) and silica gel thin layer chromatography (dichloromethane-aceton) to give 5- (5 cyanopyridine 1 2- Yl) 1- (6-methoxypyridazine-1-yl) -1H pyrazole-3-carboxylic acid methyl ester (501 mg, 42%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 4.00 (3Η, s), 4.12 (3Η, s), 7.19 (1Η, d

 Three

 , J = 9.3Hz), 7.32 (1Η, s), 7.71 (1Η, d, J = 8.3Hz), 7.98 (1H, d, J = 9.3Hz), 8.03 (1H, dd, J = 8.3, 2.2 Hz), 8.66 (1H, s).

[0419] 5) Title compound

Above 5— (5 Cyanpyridine 1-yl) 1— (6-Methoxypyridazine 3-yl)- To a mixed solution of 1H pyrazole 3 carboxylic acid methyl ester (25 lmg) in tetrahydrofuran (50 ml) and water (15 ml) was added lithium hydroxide monohydrate (32 mg) at room temperature, and the mixture was stirred overnight. To the reaction solution, a 1M aqueous hydrochloric acid solution (750 1) and a mixed solvent of black mouth form monohydrate (10: 1) and water were added for liquid separation. The organic solvent was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (183 mg, 76%) as a solid.

 ESI— MSm / z: 323 (M + H) +.

 [0420] [Reference Example 60] 5— (1-Methyl-1H-imidazole-4-yl) 1 (6 Methylpyridin 3-yl) 1H Pyrazole-3-Strong rubonic acid

 [0421] [Chemical 71]

[0422] 1) 5— (1-Methyl-1H-imidazole-4-yl) -1 (6 Methylpyridine-3-yl) 1 H Pyrazole 3 Carboxylic acid ethyl ester

Under argon atmosphere and cooling at -78 ° C, a solution of 4-acetyl- 1-methyl- 1H-imidazole (0.75 g) in tetrahydrofuran (40 ml) was added to lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 6.65 ml). Was added dropwise and stirred for 30 minutes. To the reaction mixture, jetyl oxalate (1.64 ml) was added and stirred at room temperature for 90 minutes. Water and jetyl ether were added to the reaction solution and partitioned. A 1M aqueous hydrochloric acid solution (6.70 ml) was added to the aqueous layer, and the mixture was extracted with a mixed solvent of chloroform-form methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure and 5 hydrazino 2-methylpyridine (676 mg) of Reference Example 7 were dissolved in 1M hydrochloric acid ethanol solution (40 ml), and then heated under reflux for 45 minutes. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black mouth form-methanol) to give 5- (1-methyl). 1H-imidazole 4-yl) 1 (6 methylpyridine-3-yl) 1H-pyrazole 3-ethyl rubonic acid ethyl ester (705 mg, 45%) was obtained as a red-brown solid.

'H-NMR (400MHz, CDC1) δ: 1.41 (3Η, t, J = 7.2Hz), 2.63 (3H, s), 3

 Three

 .64 (3H, s), 4.44 (2H, q, J = 7.1Hz), 6.64 (1H, s), 7.15 (1H, s), 7.26 (1H, d, J = 8.3Hz), 7.40 (1H, s), 7.78 (1H, dd, J = 8.3, 2.7Hz), 8.54 (1H, d, J = 2.7Hz).

ESI— MS m / z: 312 (M + H) ⁺ .

[0423] 2) Title compound

 5— (1-Methyl-1H-imidazole-4-yl) -1— (6-Methylpyridine-3yl) 1H Pyrazole-3—Strong rubonic acid ethyl ester (694 mg) and lithium hydroxide monohydrate (112 mg) was used to obtain the title compound (444 mg, 70%) as a solid in the same manner as in Reference Example 59, 5).

 'H-NMR (400MHz, DMSO-d) δ: 2.54 (3Η, s), 3.61 (3Η, s), 6.96 (1

 6

 H, s), 7.17 (1H, s), 7.37 (1H, d, J = 8.3Hz), 7.59 (1H, s), 7.77 (1H, dd, J = 8.3, 2.7Hz), 8.47 (1H , d, J = 2.4Hz).

 ESI— MSm / z: 284 (M + H) +.

[0424] [Reference Example 61] 1— (6-Methoxy-3 pyridyl) -5- (1-methyl-1H pyrazole

4Hil) 1H Pyrazole-3-Power rubonic acid

[0425] [Chemical 72]

1) 1-Methyl- 1H Pyrazole- 4 Carbaldehyde

Under nitrogen atmosphere, N, N dimethylformamide (54.2 ml) was mixed with oxychloride at 0 ° C. (65.3 ml) was added dropwise over 30 minutes, followed by stirring at room temperature for 1 hour. The reaction solution was stirred at 80 ° C. for 10 minutes, and 1-methylvirazole (25. Og) was added dropwise over 30 minutes. Further, the reaction solution was stirred at 85 ° C. for 1 hour, at 100 ° C. for 3 hours, and further at 115 ° C. for 1 hour. After air cooling, the reaction solution was added to ice water (11) and stirred for 20 hours. To the reaction solution, 1M sodium hydroxide aqueous solution (2 L) and chloroform were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform methanol) to give 1 methyl 1H pyrazole 4 carbaldehyde (22. lg, 66%) as an oil. .

 'H-NMR (400MHz, CDC1) δ: 3.97 (3Η, s), 7. 91 (1Η, s), 7. 96 (1H, s)

 Three

 , 9. 85 (1H, s).

 ESI-MSm / z: 111 (M + H) +.

[0427] 2) 1— (1—Methyl-1H pyrazole-4-yl) ethanol

 Methyl magnesium bromide (0.84M tetrahydrofuran solution, 250 mL) was added to a tetrahydrofuran (220 ml) solution of 1-methyl-1H pyrazole-4 monostrand rubaldehyde (22. Og) for 50 minutes under cooling at 78 ° C in an argon atmosphere. And then stirred for 20 minutes. The reaction solution was stirred at 0 ° C. for 50 minutes, and then water and chloroform were added to the reaction solution and stirred. The insoluble matter in the reaction solution was filtered off using celite. To the obtained filtrate, water and chloroform were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol monochloroform). 1- (1-methyl-1H pyrazole-4-yl) ethanol (20.2 g, 80 %) Was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.49—1.51 (3Η, m), 3.87 (3Η, s), 4.8

 Three

 7-4. 92 (1H, m), 7. 33 (1H, s), 7. 44 (1H, s).

ESI-MSm / z: 127 (M + H) ⁺ .

[0428] 3) 1— (1-Methyl 1H pyrazole-4-yl) ethanone

Under an argon atmosphere, manganese (IV) oxide (active, 209 g) was added at 0 ° C. to a solution of 1-methyl-iH pyrazole-4-yl) ethanol (20.2 g) in dichloromethane (202 mL). After stirring at room temperature for 14 hours, the insoluble matter in the reaction solution was filtered off, and the resulting filtrate was dissolved. The solvent was distilled off under reduced pressure to obtain 1- (1-methyl-1H-pyrazole-4-yl) ethanone (18. lg, 91%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.42 (3Η, s), 3.94 (3Η, s), 7.86 (1H, s)

 Three

 , 7. 89 (1H, s).

ESI-MSm / z: 125 (M + H) ⁺ .

[0429] 4) 4— (1-Methyl-1H pyrazole-4-yl) —2, 4-Dioxobutanoic acid ethyl ester

 Under an argon atmosphere, sodium ethoxide (8.77 g) in ethanol (80 ml) was added with ethyl oxalate (17.5 mL) at room temperature and stirred for 10 minutes. To the reaction solution, a solution of 1- (1-methyl 1H pyrazole 4-yl) ethanone (8.00 g) in ethanol (80 ml) was added and stirred for 90 minutes. Water and jetyl ether were added to the reaction solution to separate it. A saturated aqueous ammonium chloride solution was added to the aqueous layer, extracted with black mouth form, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4- (1-methyl-1H pyrazole-4-yl) 2,4 dioxobutanoic acid ethyl ester (11.4 g, 79%) as a solid. 'H-NMR (400MHz, CDC1) δ: 1.39—1.42 (3Η, m), 3.98 (3Η, s), 4.3

 Three

 6-4.41 (2H, m), 6.69 (1H, s), 7.98 (2H, m).

EI-MSm / z: 224 (M ⁺ ).

[0430] 5) 1— (6-Methoxy-1-pyridyl)-5- (1-Methyl 1H pyrazole-4-yl)

 -1H-pyrazole 3 carboxylic acid ethyl ester

Under an argon atmosphere, ethanol (171 ml) of the above 4- (1-methyl-1H pyrazole-4-yl) -2,4 dixobutanoic acid ethyl ester (8.55 g) and 5-hydrazino 2-methoxypyridine (5.31 g) of Reference Example 2 The solution was heated to reflux for 30 minutes. Acetic acid (10.9 ml) was added to the reaction solution, and the mixture was heated to reflux for 13 hours. After air cooling, saturated sodium hydrogen carbonate and black mouth form were added to the reaction solution, and the mixture was separated. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formacetone). 1- (6-Methoxy-1-pyridyl) -5- (1-methyl-1H pyrazol (Lu 4-yl) -1H pyrazole-3-carboxylic acid ethyl ester (11.0 g, 88%) was obtained as a solid. NMR-NMR (400MHz, CDC1) δ: 1.42 (3H, t, J = 7.2Hz), 3.86 (3H, s), 3

 Three

 .99 (3H, s), 4.44 (2H, q, J = 7.2Hz), 6.82 (1H, dd, J = 8.8, 0.7Hz), 6.96 (1H, s), 7.16 (1H, s), 7.30 (1H, m), 7.63 (1H, dd, J = 8.8, 2.7Hz), 8.21-8.22 (1H, m).

EI-MSm / z: 327 (M ⁺ ).

[0431] 6) Title compound

 1- (6-Methoxy-1-pyridyl) -5- (1-methyl-1H pyrazole-4-yl) -1-H-pyrazole-3-carboxylic acid ethyl ester (11. Og) tetrahydrofuran (110 ml) and methanol (110 ml) ) 1M sodium hydroxide aqueous solution (84. Oml) was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1M aqueous hydrochloric acid (84.0 ml), and water and chloroform were added to separate the layers. The solvent in the organic layer was distilled off under reduced pressure, and the resulting residue was filtered with the solid obtained by mixing the jetyl ether to give the title compound (8.84 g, 88%).

 'H-NMR (400MHz, DMSO-d) δ: 3.79 (3Η, s), 3.93 (3Η, s), 6.98 (1

 6

 H, d, J = 8.8Hz), 7.01 (IH, s), 7.33 (1H, s), 7.66 (1H, s), 7.80—7.8

3 (1H, m), 8.27 (1H, d, J = 2.7Hz), 12.93 (1H, br).

 EI— MSmZz: 299 (M +).

[0432] [Reference Example 62] 1— (6-Methoxy-3-pyridyl) -5 (thiazole-5 yl) 1H-pyrazole 3-carboxylic acid

[0433] [Chemical 73]

[0434] 1) 5-Acetylthiazole

1 ( ₅ thiazolyl) ethanol ( _D. s. Noyce et al., J. Org. Ch.) Under argon atmosphere em., 1973, 38, 3316, 1.70 g) in dichloromethane (34 ml) at room temperature was added acid mangan (IV) (active, 5.72 g) and stirred for 1.5 hours. ) (Activity, 5.72 g) was added and stirred for 2 hours. Furthermore, acid manganese (IV) (activity, 5.72 g) was added, and the mixture was stirred for 3.5 hours. Insoluble matter in the reaction solution was filtered off, and the solvent of the obtained filtrate was distilled off under reduced pressure to obtain 5 acetylethyl thiazole (1.17 g, 70%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.63 (3Η, m), 8.43 (1Η, s), 9.01 (1H, s

 Three

 )

EI-MSm / z: 127 (M ⁺ ).

[0435] 2) 4- (Thiazol-5 yl) -2, 4 Dioxobutanoic acid ethyl ester

 Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 9.95 ml) was added dropwise to a solution of 5 acetylthiazole (1.15 g) in tetrahydrofuran (23 ml) under an argon atmosphere at 78 ° C and stirred for 1 hour. did. To the reaction solution was added dropwise ethyl oxalate (2.46 ml), and the mixture was stirred at 78 ° C for 15 minutes, at 0 ° C for 45 minutes, and further at room temperature for 3.5 hours. Water and jetyl ether were vigorously separated into the reaction solution. Saturated salt water solution was added to the aqueous layer and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4 (thiazole-5-yl) -2,4-dioxobutanoic acid ethyl ester (1.64 g, 80%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.40—1.44 (3Η, m), 4.39—4.44 (2Η,

 Three

 m), 6.91 (1H, s), 8.57 (1H, s), 9.07 (1H, s).

EI-MSm / z: 227 (M ⁺ ).

[0436] 3) 1— (6-Methoxy-1-pyridyl) 5— (thiazole 5-yl) 1H Pyrazol lu 3-carboxylic acid ethyl ester

 Reference Example 61 5) using 4 (thiazol-5yl) 2,4 dioxobutanoic acid ethyl ester (1.63 g) and 5 hydrazino 1-methoxypyridine (1.10 g) of Reference Example 2 under an argon atmosphere In the same manner as above, 1 (6-methoxy-3-pyridyl) -5- (thiazol-5 yl) 1H pyrazole-3-power rubonic acid ethyl ester (1.16 g, 49%) was obtained as a solid.

'H-NMR (400MHz, CDC1) δ: 1.43 (3Η, t, J = 7.2Hz), 3.99 (3H, m), 4.46 (2H, q, J = 7.2Hz), 6.81— 6.84 (1H, m), 7.17 (1H, m), 7.60— 7.63 (1H, m), 7.79 (1H, s), 8.19 ( 1H, d, J = 2.7Hz), 8.78 (1H, s).

EI-MSm / z: 330 (M ⁺ ).

[0437] 4) Title compound

 1- (6-Methoxy-3-pyridyl) -5- (thiazol 5-yl) 1H Pyrazo 1-lu 3-Strong rubonic acid ethyl ester (1.15 g) is used in the same manner as in Reference Example 61-6) Gave the title compound (0.710 g, 68%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.94 (3Η, s), 7.00 (1Η, d, J = 8.8H

 6

 z), 7.32 (1H, s), 7.85 (1H, dd, J = 8.8, 2.7Hz), 8.12 (1H, s), 8.31 (1

H, d, J = 2.7Hz), 9.08 (1H, s), 13. 10 (1H, br).

EI-MSm / z: 302 (M ⁺ ).

[0438] [Reference Example 63] 1— (6-Methoxy-3-pyridyl) -5 (thiazole-2-yl) 1H-pyrazole 3-carboxylic acid

[0439] [Chemical 74]

[0440] 1) 4 (Thiazole-2-yl) -2,4 Dioxobutanoic acid ethyl ester

 2 of Reference Example 62 using 2 acetylethyl thiazole (2.50 g), lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 21.6 ml), and jetyl oxalate (5.3 4 ml) under an argon atmosphere. ) To give 4 (thiazole-2-yl) 2,4-dioxobutanoic acid ethyl ester (3.33 g, 74%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.39—1.43 (3Η, m), 4.38—4.43 (2Η,

 Three

 m), 7.41 (1H, s), 7.77— 7.78 (1H, m), 8.08 (1H, d, J = 2.9Hz).

EI-MSm / z: 227 (M ⁺ ). [0441] 2) 1— (6-Methoxy-1-pyridyl) -5- (thiazol 2-yl) 1H Pyrazol lu 3-carboxylic acid ethyl ester

 [0442] Using the above 4 (thiazole-2-yl) 2,4 dioxobutanoic acid ethyl ester (3.32 g) and 5 hydrazino 2-methoxypyridine (2.24) of Reference Example 2 under an argon atmosphere, In the same manner as in 5), 1 (6-methoxy-3-pyridyl) -5- (thiazol-2-yl) 1H pyrazole-3-streptyl carboxylic acid ethyl ester (1.22 g, 25%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41— 1.45 (3Η, m), 3.99 (3Η, s), 4.4

 Three

 3-4.49 (2H, m), 6.83 (1H, dd, J = 8.8, 0.7Hz), 7.36— 7.37 (1H, m), 7.42 (1H, m), 7.70 (1H, dd, J = 8.8, 2.7 Hz), 7.81—7.82 (1H, m), 8. 26 (1H, d, J = 2.7Hz).

 FAB MSm / z: 331 (M + H) +.

[0443] 3) Title compound

 1- (6-Methoxy-3-pyridyl) -5- (thiazol 2-yl) 1H Pyrazo 1-lu 3-Strong rubonic acid ethyl ester (1.21 g) was used in the same manner as in Reference Example 61-6) The title compound (0.951 g, 86%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.94 (3Η, s), 7.00 (1Η, dd, J = 8.8

 6

 , 0.5Hz), 7.39 (1H, s), 7.84— 7.93 (3H, m), 8.36 (1H, dd, J = 2.7, 0.

5Hz), 13.21 (1H, br).

 FAB MSm / z: 303 (M + H) +.

[0444] [Reference Example 64] 1— (6-Methoxy-3 pyridyl) -5- (thiazole 4-yl) 1H-pyrazole 3-carboxylic acid

[0445] [Chemical 75]

[0446] 1) (4 チアゾリル)メタノール

[0446] 1) (4 Thiazolyl) methanol

 To 4 (chloromethyl) thiazole hydrochloride (47.2 g) was added 1M aqueous sodium hydroxide solution (27 8 ml), and the mixture was heated to reflux for 75 minutes. After air cooling, 1M sodium hydroxide (278 ml) was further added, and the mixture was extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formethanol) to give (4 thiazolyl) methanol (21.8 g, 68%) as an oil. The

'H-NMR (400MHz, CDC1) δ: 3.41 (1Η, s), 4. 83 (2H, m), 7. 27—7.2

 Three

 8 (1H, m), 8. 81 (1H, m).

 FAB— MSm / z: 116 (M + H) +.

[0447] 2) 4 Formylthiazole

 Under an argon atmosphere, to the solution of (4 thiazolyl) methanol (21.8 g) in dichloromethane (218 ml) was added acid manganese (IV) (active, 247 g) at 0 ° C., and the mixture was stirred for 21 hours. The insoluble material in the reaction solution was filtered off, and the solvent of the obtained filtrate was distilled off under reduced pressure to obtain 4 formylthiazole (6.91 g, 32%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 8. 27 (1Η, d, J = 2. ΟΗζ), 8. 93 (1Η, d, J

 Three

 = 2. OHz), 10. 14 (1H, s).

 FAB MSm / z: 114 (M + H) +.

[0448] 3) 1- (4 thiazolyl) ethanol

 Under argon atmosphere, methylmagnesium bromide (0.89M tetrahydrofuran solution, 72. Oml) was added to a solution of 4 formylthiazole (6.90 g) in tetrahydrofuran (138 ml) at 78 ° C over 30 minutes. The solution was added dropwise, stirred for 30 minutes, and then stirred at 0 ° C for 150 minutes. Water was added to the reaction solution, and insoluble matters in the reaction solution were filtered off using celite. To the obtained filtrate, water and chloroform were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black form-methanol). 1- (4 thiazolyl) ethanol (7.46 g, 95%) was converted into an oily product. I got it.

'H-NMR (400MHz, CDC1) δ: 1. 60—1.61 (3Η, m), 2. 73 (1Η, s), 5.0 6-5.10 (1H, m), 7.22-7.23 (1H, m), 8.80 (1H, d, J = 2.0Hz).

 FAB MSm / z: 130 (M + H) +.

[0449] 4) 4 Acetylthiazole

 Under an argon atmosphere, acid manganese (IV) (active, 75.2 g) was added to a dichloromethane (149 ml) solution of the above 11 (41-thiazolyl) ethanol (7.45 g) at 0 ° C. and stirred for 6 hours. Insoluble matter in the reaction solution was filtered off, and the solvent of the obtained filtrate was distilled off under reduced pressure to obtain 4-acetylethylazole (6.94 g, 95%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.71 (3Η, s), 8.21—8.22 (1Η, m), 8.8

 Three

 4 (1Η, m).

ESI-MSm / z: 128 (M + H) ⁺ .

[0450] 5) 4- (Thiazol-4-yl) -2,4 dioxobutanoic acid ethyl ester

 Under an argon atmosphere, diethyl oxalate (7.37 ml) was added to a solution of sodium ethoxide (3.69 g) in ethanol (35 ml) at room temperature and stirred for 10 minutes. To the reaction solution, a solution of the above 4-acetylthiazole (3.45 g) in ethanol (35 ml) was stirred for 3 hours. Water and jetyl ether were vigorously separated into the reaction solution. A saturated aqueous ammonium chloride solution was added to the aqueous layer, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 4 (thiazol-4-yl) 2,4 diethylbutanoic acid ethyl ester (5.27 g, 85%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41 (3Η, t, J = 7.2Hz), 4.40 (2H, q, J

 Three

 = 7.2Hz), 7.41 (1H, s), 8.33- 8.34 (1H, m), 8.89 (1H, m), 14.69 (1 H, br).

EI-MSm / z: 227 (M ⁺ ).

[0451] 6) 1— (6-Methoxy-1-pyridyl) -5- (thiazol 4-yl) 1H Pyrazol lu 3-carboxylic acid ethyl ester

Reference Example 61-5) using the above 4 (thiazole-4-yl) 2,4 dioxobutanoic acid ethyl ester (5.26 g) and Reference Example 2 5 hydrazino-2-methoxypyridine (3.22 g) under an argon atmosphere 1 (6-Methoxy-3-pyridyl) -5- (thiazol-4-yl) 1H Pyrazole-3-power rubonic acid ethyl ester (5.89 g, 77%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.41— 1.44 (3Η, m), 3.98 (3Η, s), 4.4

 Three

 3-4.48 (2H, m), 6.82 (1H, d, J = 8.8Hz), 7.15 (1H, d, J = 2.OHz), 7. 31 (1H, s), 7.69 (1H, dd, J = 8.8, 2.7Hz), 8.18 (1H, d, J = 2.7Hz), 8. 79 (1H, d, J = 2. OHz).

EI-MSm / z: 330 (M ⁺ ).

[0452] 7) Title compound

 1- (6-Methoxy-3-pyridyl) -5- (thiazole 4-yl) 1H Pyrazo 1-lu 3-Strong rubonic acid ethyl ester (5.88) was used in the same manner as in Reference Example 61, 6). The title compound (5.16 g, 96%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.91 (3Η, s), 6.94 (1Η, d, J = 8.8H

 6

 z), 7.27 (1H, s), 7.79 (1H, dd, J = 8.8, 2.7Hz), 7.85 (1H, m), 8.22 (1

H, d, J = 2.7Hz), 9.11-9.12 (1H, m), 13.07 (1H, br).

EI-MSm / z: 302 (M ⁺ ).

[0453] [Reference Example 65] 1— (6-Methoxy-3-pyridyl) -5- (6-methyl-3-pyridyl) 1H pyrazonole 3-force norebonic acid

[0454] [Chem 76]

1) 6 Methylpyridine-3-strong rubonic acid N-methoxy-N-methylamide

 Using 6-methylnicotinic acid (20. Og) and N, O dimethylhydroxyamine hydrochloride (14.2 g) in the same manner as 1) of Reference Example 31, 6-methylpyridine mono-3-carboxylic acid N-methoxy-1-N-methylamide (17.5 g, 67%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 2.60 (3Η, s), 3.38 (3Η, s), 3.56 (3H, s)

 Three

, 7.21 (1H, d, J = 8.1Hz), 7.93— 7.95 (1H, m), 8.86 (1H, d, J = 2. OHz ).

 EI— MSmZz: 180 (M +).

[0456] 2) 1- (6-Methinore 3 Pyridinore)-1 Ethanone

 In the same manner as in Reference Example 8 2) using 6 methylpyridine-3-strong rubonic acid N-methoxy-N-methylamide (17.5 g) and methyllithium (0.98 M in ethyl ether solution, 104 ml), 1 — (6-Methyl-3-pyridyl) 1-ethanone (12.3 g, 94%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.61 (3Η, s), 2.62 (3Η, s), 7.25— 7.27

 Three

 (1H, m), 8.11-8.13 (1H, m), 9.04 (1H, d, J = 2.2Hz).

ESI-MSm / z: 136 (M + H) ⁺ .

[0457] 3) 4- (6-Methyl-3-pyridyl) 2, 4 Dioxobutanoic acid ethyl ester

 Using the above 1- (6-methyl-3-pyridyl) 1-ethanone (6.29 g), lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 51.2 ml) and oxalate jetyl (12.6 ml) In the same manner as in 8-3), 4- (6-methyl-3-pyridyl) -2,4-dioxobutanoic acid ethyl ester (5.08 g, 47%) was obtained as a solid. 'H-NMR (400MHz, CDC1) δ: 1.39—1.42 (3Η, m), 2.65 (3Η, s), 4.3

 Three

 7-4.42 (2H, m), 7.03 (1H, s), 7.30 (1H, d, J = 8.3Hz), 8.13-8.16 (1H, m), 9.07 (1H, d, J = 2.2Hz).

 EI— MSmZz: 235 (M +).

[0458] 4) 1— (6-Methoxy-3-pyridyl) 5— (6-Methyl-3-pyridyl) 1H Pyrazole 3-Carboxylic acid ethyl ester

Ethanol (101 ml) of 4- (6-methyl-3-pyridyl) -2,4-dioxobutanoic acid ethinoleestenole (5.06 g) and 5 hydrazino 2-methoxypyridine (2.99 g) of Reference Example 2 in an argon atmosphere After the solution was heated to reflux for 30 minutes, acetic acid (6.16 ml) was added to the reaction solution and heated to reflux for 42 hours. After air cooling, the reaction solution was separated with saturated sodium hydrogen carbonate and black mouth form, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formacetone), 1- (6-methoxy-1-pyridyl) -5- (6-methyl-3-pyridyl) 1H Pilazo Lou 3 -strength rubonic acid ethyl ester (4.68 g, 64%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.41—1.44 (3Η, m), 2.57 (3Η, s), 3.9

 Three

 4 (3H, s), 4.43-4.49 (2H, m), 6.77 (1H, d, J = 8.8Hz), 7.08 (1H, s), 7.13 (1H, d, J = 8.1Hz), 7.39 (1H, dd, J = 8.1, 2.2Hz), 7.59 (1H, dd, J = 8.8, 2.7Hz), 8.08 (1H, d, J = 2.7Hz), 8.41 (1H, d, J = 2.2Hz) .

 EI— MSmZz: 338 (M +).

[0459] 5) Title compound

 1- (6-Methoxy-3-pyridyl) -5- (6-methyl-3-pyridyl) 1H-virazole 3 Carboxylic acid ethyl ester (1.10 g) in tetrahydrofuran (22 ml) and methanol (22 ml) in a mixed solution at room temperature. 1M sodium hydroxide aqueous solution (8.13ml) was stirred for 4.5 hours. The reaction mixture was neutralized with 1M aqueous hydrochloric acid (8.13 ml), and water and chloroform were added to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was covered with jetyl ether, and the resulting solid was collected by filtration to give the title compound (0.873 g, 86%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.47 (3Η, s), 3.89 (3Η, s), 6.92 (1

 6

 H, d, J = 9.0Hz), 7.16 (1H, s), 7.26 (1H, d, J = 8.3Hz), 7.53-7.56 (1

H, m), 7.74-7.77 (1H, m), 8.17 (1H, d, J = 2.7Hz), 8.40 (1H, d, J = 2

.2Hz), 13.05 (1H, br).

EI-MSm / z: 310 (M ⁺ ).

[0460] [Reference Example 66] 5— (6-tert-butoxycarbo-lumino-3-pyridyl) -1 (6-methoxy-3-pyridyl) 1H pyrazole 3-carboxylic acid

[0461] [Chemical 77]

[0462] 1)5- (6—カルボキシ一 3 ピリジル） 1— (6—メトキシ一 3 ピリジル） 1H ピ ラゾール 3—カルボン酸ェチルエステル

[0462] 1) 5- (6-Carboxy-3-pyridyl) 1- (6-Methoxy-1-pyridyl) 1H pyrazole 3-carboxylic acid ethyl ester

 Reference Example 65, 4) 1- (6-methoxy-3-pyridyl) -5- (6-methyl-3-pyridyl) 1 1H pyrazole-3-strength rubonic acid ethyl ester (3.45 g) and selenium dioxide (4.53 g) In the same manner as in Reference Example 42, 1), 5- (6 carboxy-3 pyridyl) -1- (6-methoxy-3-pyridyl) -1H pyrazole-3-ethyl carboxylic acid ester (3.86 g, quantitative) Was obtained as an amorphous substance.

 'H-NMR (400MHz, DMSO-d) δ: 1.34 (3Η, t, J = 7.1Hz), 3.90 (3H,

 6

 s), 4.36 (2H, q, J = 7.1Hz), 6.95 (1H, d, J = 8.8Hz), 7.36—7.40 (1H, m), 7.79-7.87 (2H, m), 8.03 (1H, d , J = 8.1Hz), 8.22 (1H, d, J = 2.7 Hz), 8.65 (1H, m).

 EI— MSmZz: 368 (M +).

[0463] 2) 5- (6-tert-Butoxycarbo-lamino 3-pyridyl) -1- (6-methoxy-3-pyridyl) 1H pyrazole 3 carboxylic acid ethyl ester

 5— (6-Carboxy-3-pyridyl) 1- (6-Methoxy-1-pyridyl) 1H —Pyrazole-3-carboxylic acid ethyl ester (3.84 g), diphenylphosphoryl azide (2.42 ml) and tert-butanol (2 In the same manner as in Reference Example 42, 2), 5— (6— tert-butoxycarbo-lamino—3-pyridyl) —1— (6-methoxy-3 pyridyl) —1H pyrazole-3 —Carboxylic acid ethyl ester (2.56 g, 57%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.41— 1.45 (3Η, m), 1.52 (9Η, s), 3.9

 Three

 5 (3H, s), 4.43-4.49 (2H, m), 6.75— 6.78 (1H, m), 7.05 (1H, s), 7. 37-7.46 (2H, m), 7.58 (1H, dd, J = 8.8, 2.7Hz), 7.95 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 2.2Hz), 8.18-8.19 (1H, m).

EI-MSm / z: 439 (M ⁺ ).

[0464] 3) Title compound

Using 5- (6- tert-butoxycarbo-lamino 3-pyridyl) -1- (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (2.55 g) Then, the title compound (1.75 g, 73%) was obtained as a solid in the same manner as in Method 4) B of Reference Example 4.

 'H-NMR (400MHz, DMSO-d) δ: 1.47 (9Η, s), 3.89 (3Η, s), 6.92 (1

 6

 H, d, J = 8.8Hz), 7.12 (1H, s), 7.59 (1H, dd, J = 8.8, 2.4Hz), 7.73— 7

.78 (2H, m), 8.16— 8. 18 (2H, m), 9.95 (1H, s), 13.01 (1H, br).

EI-MSm / z: 411 (M ⁺ ).

[0465] [Reference Example 67] 1- (6-Methoxypyridazine-3 yl) -5- (6-Methyl-3 pyridyl)

 -1H-pyrazole 3 carboxylic acid

[0466] [Chemical 78]

[0467] 1) 4— (6-Methyl-3 pyridyl) 2, 4 Dioxobutanoic acid methyl ester

 Using Reference Example 65, 2) 1- (6-methyl-3-pyridyl) 1-ethanone (6.00 g), lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 48.8 ml) and dimethyl oxalate (10.5 g) Thus, in the same manner as in Reference Example 8 3), 4- (6-methyl-3-pyridyl) 2,4 dioxobutanoic acid methyl ester (5.63 g, 57%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.66 (3Η, s), 3.96 (3Η, s), 7.05 (1H, s)

 Three

 , 7.31 (1H, d, J = 8.3Hz), 8.15— 8.17 (1H, m), 9.08 (1H, d, J = 2.2Hz).

 EI-MSm / z: 221 (M +).

[0468] 2) 1— (6 Black 3-ringidazil) 5— (6-Methyl 3-pyridyl) 1H-virazole 3-carboxylic acid methyl ester

4- (6-Methyl-3-pyridyl) -2,4 dioxobutanoic acid methyl ester (5. 62 g) and 3 black mouth 6 hydrazinopyridazine (3.67 g) in the same manner as 3) of Method B in Reference Example 4 and 1— (6 black mouth 3 pyridazil) —5— ( 6-methyl-3-pyridyl) -1) pyrazole-3-carboxylic acid methyl ester (4.82 g, 58%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.60 (3Η, s), 4.01 (3Η, m), 7.07—7.0

 Three

 8 (1H, m), 7.21 (1H, d, J = 8.1Hz), 7.64— 7.67 (1H, m), 7.69 (1H, dd, J = 9.0, 1.0Hz), 8.19 (1H, dd, J = 9.0, 1. OHz), 8.44— 8.45 (1H, m)

FAB MSm / z: 330 (M + H) +.

[0469] 3) Title compound

In an argon atmosphere, the above 1 (chloro-pyridazil) ( _6- methyl- ₃

-Pyridyl) 1M Pyrazole-3-carboxylic acid methyl ester (4.81 g) in methanol (96 ml) was added with sodium methoxide (2.36 g) at room temperature and heated to reflux for 100 minutes. After air cooling, water (96 ml) was added to the reaction solution and stirred for 30 minutes. To the reaction solution was added 1M aqueous hydrochloric acid solution (29.2 ml), and the resulting solid was collected by filtration to give the title compound (4.40 g, 97%). 'H-NMR (400MHz, DMSO-d) δ: 2.49 (3Η, s), 4.03 (3Η, s), 7.18 (1

 6

 H, s), 7.26 (1H, d, J = 7.8Hz), 7.51 (1H, d, J = 9.3Hz), 7.60—7.62 (1

H, m), 8.05 (1H, d, J = 9.3Hz), 8.42 (1H, m), 13.22 (1H, br).

 FAB— MSm / z: 312 (M + H) +.

[0470] [Reference Example 68] 5- (6-tert-butoxycarbo-lumino-3-pyridyl) -1 (6-methoxypyrididazine-3-yl) -1H pyrazole-3-carboxylic acid

[0471] [Chemical 79]

[0472] 1) 1— (6—メトキシ一 3 ピリダジ -ル） 5— (6—メチル 3 ピリジル） 1H ピ ラゾール 3—カルボン酸メチルエステル

[0472] 1) 1— (6-Methoxy-1-pyridazil) 5— (6-Methyl-3-pyridyl) 1H-Pyrazole 3-carboxylic acid methyl ester

 In an argon atmosphere, 1- (6-Methoxy-3-pyridazil) 5- (6-Methyl-1-pyridyl) 1-H pyrazole-3-carboxylic acid (3. llg) in methanol (31 ml) and dichloromethane ( 62 ml) (trimethylsilyl) diazomethane (2.OM in hexane, 12. Oml) was added to the mixed suspension at 0 ° C., and the mixture was stirred for 90 minutes and then at room temperature for 22 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-acetone) to give 1- (6-methoxy-3-pyridazil) -5- (6-methyl). —3 Pyridyl) -1H pyrazole-3-carboxylic acid methyl ester (3.35 g, quantitative) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.59 (3Η, s), 4.00 (3Η, s), 4.12 (3H, s)

 Three

 , 7.08 (1H, s), 7.14-7.21 (2H, m), 7.63 (1H, dd, J = 7.9, 2.3Hz), 7. 96-7.98 (1H, m), 8.41 (1H, dd, J = 2.3, 0.6Hz).

 FAB MSm / z: 326 (M + H) +.

[0473] 2) 5- (6-Carboxy-3 pyridyl) -1-(6-methoxy-3 pyridazil)-1H pyrazole 3-carboxylic acid methyl ester

 Using the above 1- (6-methoxy-3pyridazil) -5- (6-methyl-3pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (3.27 g) and selenium dioxide (4.46 g) In the same manner as in Example 42, 1), 5- (6 carboxy 3 pyridyl) 1 (6-methoxy-3 pyridazil) 1H pyrazole-3-carboxylic acid methyl ester (2.72 g, 76%) was obtained as a solid. .

 'H-NMR (400MHz, DMSO-d) δ: 3.90 (3Η, s), 4.02 (3Η, s), 7.43 (1

 6

 H, s), 7.54 (1H, d, J = 9.3Hz), 7.93— 7.96 (1H, m), 8.03— 8.05 (1H, m), 8. 13 (1H, d, J = 9.3Hz), 8.70 (1H, d, J = 2.0Hz), 13.35 (1H, s). FAB MSm / z: 356 (M + H) +.

[0474] 3) 5- (6-tert-Butoxycarbo-lamino 3-pyridyl) -1- (6-methoxy-3-pyridazil) 1H pyrazole 3 carboxylic acid methyl ester

5— (6-Carboxy-3-pyridyl) -1— (6-Methoxypyridazine-3-yl) — 1H Pyrazole-3-carboxylic acid methyl ester (2.70 g), diphenylphosphoryl azide (1.80 ml) and tert-butanol (1.60 ml) were used in the same manner as in Reference Example 42, 2). — Tert-Butoxycarbolamino 3-pyridyl) -1 (6-methoxy-3-pyridazil) 1H Pyrazole 3 carboxylic acid methyl ester (1.75 g, 54%) was obtained as an amorphous substance.

 'H-NMR (400MHz, CDCl) δ: 1.52 (9Η, s), 3.99 (3Η, s), 4.12 (3H, s)

 Three

 , 7.04 (1H, s), 7.14 (1H, d, J = 9.3Hz), 7.61— 7.64 (1H, m), 7.92— 7.99 (3H, m), 8.27 (1H, d, J = 2.2Hz ).

EI-MSm / z: 426 (M ⁺ ).

[0475] 4) 5- (6— tert-Butoxycarbolamino-1-pyridyl) 1- (6-methoxy-1-3-pyridazil) 1H pyrazole 3 carboxylic acid

 Method B of Reference Example 4 using the above 5- (6-tert-butoxycarbolamino 3-pyridyl) -1- (6-methoxy-3-pyridazil) 1H pyrazole 3 carboxylic acid methyl ester (1.74 g) The title compound (1.32 g, 79%) was obtained as a solid in the same manner as 4).

 'H-NMR (400MHz, DMSO-d) δ: 1.48 (9Η, s), 4.04 (3Η, s), 7.16 (1

 6

 H, s), 7.50 (1H, d, J = 9.3Hz), 7.64— 7.66 (1H, m), 7.77— 7.79 (1H, m), 8.04 (1H, d, J = 9.3Hz), 8.23— 8.24 (1H, m), 9.94 (1H, s), 13.12 (1H, br).

 FAB— MSm / z: 413 (M + H) +.

[0476] [Reference Example 69] 5- (1H-imidazole-4-yl) -1 (6-methoxy-3-pyridyl)

 -1H-pyrazole 3 carboxylic acid

[0477] [Chemical 80]

[0478] 1) 4— (1—トリフエ-ルメチル— 1H—イミダゾール— 4—ィル）—2, 4 ジォキソブタ ン酸ェチルエステル

[0478] 1) 4— (1-Triphenylmethyl-1H-imidazole-4-yl) -2, 4 Dioxobutanoic acid ethyl ester

 4-acetyl-1-trimethyl-lH-imidazole (N. Matsunaga et al., Bio org. Med. Chem., 2004, 12, 2251, 2.48 g), lithium bis (trimethylsilyl) amide (1.0 M in tetrahydrofuran, 7. (74 ml) and ethyl oxalate (1.91 ml) in the same manner as in Reference Example 8 3), 4- (1-Trimethyl-methyl-1H-imidazol-4-yl) 2, 4 Dioxobutanoic acid ethyl ester (3.26 g, quantitative) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.36—1.40 (3Η, m), 4.34—4.39 (2Η,

 Three

 m), 6. 92 (1H, m), 7. 11— 7. 17 (6H, m), 7. 26— 7. 39 (9H, m), 7. 51 (1 H, m), 7. 70 (1H, m).

 [0479] 2) 5-(1H-imidazole-4-yl) -1-1- (6-methoxy-3-pyridyl) -1H pyrazole 3-carboxylic acid ethyl ester

 Ethanol of the above 4- (1-trimethyl- 1H-imidazole-4-yl) -2,4 dixobutanoic acid ethyl ester (3.25 g) and 5 hydrazino 2-methoxypyridine (0.979 g) of Reference Example 2 The (65 ml) solution was heated to reflux for 49 hours. After cooling with air, water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black mouth form-acetone) to give 1- (6-methoxy-3-pyridyl) -5- (1-triphenyl). -Lumethyl-1Himidazole-4-yl) 1H-Pyrazole-3-r-rubonic acid ethyl ester (0.865 g) was obtained as an amorphous substance. Furthermore, 5- (1H-imidazole 4-yl) 1- (6-methoxy-1-pyridyl) 1H-pyrazole 3-carbonic acid ethyl ester (0.367 g) was obtained as an oil from another elution fraction. .

Under an argon atmosphere, the 1- ₍₆ - methoxy - ₃ - pyridyl) - ₅ - - bird whistle - Rume Chiru 1H- dichloromethane (17 ml imidazole -4 I le) IH Pirazoru 3- force carboxylic acid Echirue ester (0. 860 g)) Trifluoroacetic acid (8.5 ml) was added to the solution at room temperature and stirred for 3.5 hours. A saturated aqueous sodium bicarbonate solution and black mouth form were separated into the reaction solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (black mouth form monoacetone).

, 5- (1H-imidazole-4-yl) 1- (6-methoxy-1-pyridyl) 1H-virazol-3-strong rubonic acid ethyl ester (0.385 g) was obtained as a solid. Combined with the amount obtained above, 5- (1H-imidazol-4-yl) -1- (6-methoxy-3-pyridyl) 1 1H pyrazole-3-strong rubonic acid ethyl ester (0.752 g, 19%) was obtained. . 'H-NMR (400MHz, CDC1) δ: 1.39—1.43 (3Η, m), 3.97 (3Η, s), 4.4

 Three

 1-4.46 (2H, m), 6.72 (1H, d, J = l.0Hz), 6.81 (1H, d, J = 8.8Hz), 7.20 (1H, s), 7.63 (1H, d, J = l.0Hz), 7.69 (1H, dd, J = 8.8, 2.7Hz), 8.23 (1H, d, J = 2.7Hz).

EI-MSm / z: 313 (M ⁺ ).

[0480] 3) Title compound

 4 of the above-mentioned 5- (1H-imidazole-4-yl) -1- (6-methoxy-3-pyridyl) -1H-pyrazole-3-strong rubonic acid ethyl ester (0.742 g) ) To give the title compound (0.449 g, 66%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.90 (3Η, s), 6.76 (1Η, s), 6.83—

 6

 6.89 (2H, m), 7.64 (1H, m), 7.74 (1H, dd, J = 8.8, 2.9Hz), 8.21— 8.

22 (1H, m), 12.50 (1H, br).

 EI— MSmZz: 285 (M +).

[0481] [Reference Example 70] 1— (6-Methoxy-3 pyridyl) -5— (1H pyrazole-4-yl)

1H-pyrazole 3 carboxylic acid

[0482] [Chemical 81]

1) 1 Triphenylmethyl- 1H pyrazole- 4 strength rubonic acid ethyl ester Under argon atmosphere, 1H pyrazole- 4 strength rubonic acid ethyl ester (W. Holzer J. Heterocyclic. Chem., 1993, 30, 865, 9.62 g) and triethylamine (9.57 ml) in N, N dimethylformamide (96 ml) at room temperature with triphenylmethyl bromide (22.2 g). Stir for 3 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the resulting residue, and the resulting solid was collected by filtration. 1-Triphenylmethyl-1H-pyrazole 4 carboxylic acid ethyl ester (16. lg , 61%).

 'H-NMR (400MHz, CDC1) δ: 1.30—1.34 (3Η, m), 4.24—4.30 (2Η,

 Three

 m), 7.11-7.15 (6H, m), 7.31—7.34 (9H, m), 7.93 (1H, s), 8.04 (1H, s).

EI-MSm / z: 382 (M ⁺ ).

[0484] 2) 1-Trimethyl- 1H-Pyrazole-4-carboxylic acid

 Add 1 M sodium hydroxide aqueous solution (105 ml) at room temperature to a mixed solution of 1-trimethyl-methyl 1H pyrazole 4 carboxylic acid ethyl ester (1 6. lg) in tetrahydrofuran (161 ml) and methanol (161 ml) for 3.5 hours. Stir. The reaction solution was neutralized with 1M aqueous hydrochloric acid solution (105 ml), and the resulting solid was collected by filtration and mixed with 1-trimethyl-methyl- 1H-pyrazole- 4 rubonic acid methyl ester as the main component (15.4 g) was obtained. This mixture of 1-trimethyl-methyl 1H pyrazole 4 carboxylic acid methyl ester (15.4 g) in tetrahydrofuran (200 ml) was added to a solution of lithium hydroxide monohydrate (2.12 g) in water (100 ml) at room temperature. ) The solution was added dropwise, stirred at room temperature for 2 hours, then stirred at 60 ° C for 2 hours and further at 90 ° C for 2 hours. After air cooling, 1M aqueous hydrochloric acid solution (50.5 ml) was neutralized at 0 ° C., and water and a mixed solvent of chloroform and methanol (10: 1) were vigorously separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 1-triphenylmethyl- 1H pyrazole-4 monostrength rubonic acid (14.3 g, 96%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 7.05— 7.08 (6Η, m), 7.38— 7.41 (

 6

 9mm, m), 7.72 (1H, s), 8.01 (1H, s), 12.54 (1H, br).

EI-MSm / z: 354 (M ⁺ ).

[0485] 3) 1-Trifluoromethyl mono 1H Pyrazole mono 4-Carboxylic acid N-Methoxy mono N-methyl amide Using the above 1-trimethyl- 1H pyrazole-4-carboxylic acid (14.3 g) and N, O-dimethylhydroxylamine hydrochloride (4.33 g) in the same manner as in Reference Example 8 1), 1-Triphenylmethyl 1 H pyrazole 4 carboxylic acid N-methoxy N methyl amide (14.4 g, 90%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.29 (3Η, s), 3.62 (3Η, s), 7.13— 7.18

 Three

 (6H, m), 7.28-7.33 (9H, m), 7.97 (1H, s), 8.11 (1H, s).

EI-MSm / z: 397 (M ⁺ ).

[0486] 4) 4-Acetyl 1 triphenylmethyl 1H pyrazole

 1 Triphenylmethyl 1H Pyrazole 4 Carboxylic acid N-Methoxy-N-methylamide (14.4g) and methyllithium (0.98M jetyl ether solution, 38.8ml) The method yielded 4-acetyl-1-trimethyl-1-H pyrazole (11.7 g, 91%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.40 (3Η, s), 7.11-7.15 (6Η, m), 7.2

 Three

9-7.35 (9H, m), 7.93 (1H, d, J = 0.7Hz), 8.04 (1H, d, J = 0.7Hz) .EI-MSm / z: 352 (M ⁺ ).

[0487] 5) 4- (1-Trimethyl-methyl 1H pyrazole 4-yl) 2, 4 Dioxobutanoic acid ethyl ester

 Using 4 acetyl-1-trimethyl- 1H pyrazole (5.85 g), lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 18.3 mL) and jetyl oxalate (4.51 ml), In the same manner, 41- (11-trimethyl-1H pyrazole-4-yl) -2,4-dioxobutanoic acid ethyl ester (6.03 g, 80%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.37—1.41 (3Η, m), 4.34—4.40 (2Η,

 Three

 m), 6.65 (1H, m), 7.12-7.16 (6H, m), 7.31- 7.36 (9H, m), 8.02 (1 H, s), 8.12 (1H, s).

EI-MSm / z: 452 (M ⁺ ).

[0488] 6) 1— (6-Methoxy-1-pyridyl) 5-— (1H-pyrazole 4-yl) 1H-virazole 3-carboxylic acid ethyl ester 4- (1-Trimethyl- 1H-pyrazole-4-yl) -2, 4 dioxobutanoic acid ethyl ester (6.02 g) and 5 hydrazino 2-methoxypyridine (2.04 g) in Reference Example 2 ( The solution was heated to reflux for 38 hours. After air cooling, the solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform formacetone). 1- (6-Methoxy-3-pyridyl) -5- (1 -Triphenyl-methyl- 1H-pyrazole-4-yl) 1H-pyrazole-3-strong rubonic acid ethyl ester (2.24 g) was obtained as an amorphous substance. Furthermore, 1- (6-methoxy-1-3-pyridyl) -5- (1H pyrazole-4-yl) -1H pyrazole-3-carboxylic acid ethyl ester (1.17 g) was obtained as an amorphous substance from another elution fraction. .

Under an argon atmosphere, the 1- ₍₆ - methoxy - ₃ - pyridyl) - ₅ - - bird whistle - Rume Chiru 1H Pirazoru 4 I le) 1H Pirazoru 3- dichloromethane force carboxylic acid Echiruesu ether (2. 23 g) (44 ml) solution Then, trifluoroacetic acid (22 ml) was added at room temperature and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-acetone). 1- (6-Methoxy-1-pyridyl) 5- (1H pyrazole-1-4- 1) 1H Pyrazole 3-force rubonic acid ethyl ester (0.830 g) was obtained as an amorphous substance. Combined with the amount obtained above, 1- (6-methoxy-3-pyridyl) -5- (1H pyrazole-4-yl) 1H pyrazole-3-strength rubonic acid ethyl ester (2.00 g, 27%) was obtained.

'H-NMR (400MHz, CDC1) δ: 1.40—1.44 (3Η, m), 3.98 (3Η, m), 4.

 Three

 42-4. 47 (2H, m), 6. 82 (1H, d, J = 8.8Hz), 7. 01 (1H, m), 7. 42 (2H, m), 7. 62-7 65 (1H, m), 8.21 (1H, d, J = 2.7Hz).

EI-MSm / z: 313 (M ⁺ ).

7) Title compound

4 of the above 1- (6-methoxy-1-pyridyl) -5- (1H-pyrazole-1-4-yl) 1H-pyrazole-3-strong rubonic acid ethyl ester (2.00 g) In a similar manner, the title compound (1.29 g, 71%) was obtained as a solid. NMR-NMR (400MHz, DMSO— d) δ: 3.93 (3H, s), 6. 98 (1H, d, J = 8.8H

 6

 z), 7. 04 (1H, m), 7. 53 (2H, br), 7. 80— 7. 83 (1H, m), 8. 26 (1H, d, J =

2.7Hz), 13.00 (1H, br).

 EI— MSmZz: 285 (M +).

[0490] [Reference Example 71] Piperidine 2-force rubonic acid amide

[0491] [Chemical 82]

[0492] N-Benzyloxycarbo-rubiperidine 2-Strong rubonic acid (2. Og), 1-Hydroxybenzotriazole (1.6 g), 1- (3 Dimethylaminopropyl) 3 Ethylcarbodiimide hydrochloride (2 Concentrated aqueous ammonia (3 ml) and triethylamine (2 ml) were added to a solution of 3 g) in dichloromethane (20 ml) at room temperature, and the mixture was stirred for 3 days. Water and dichloromethane were added to the reaction solution and separated. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, 10% palladium on carbon (lg, 50% wet) was added to a solution of the residue obtained in methanol (30 ml), and the mixture was stirred for 20 hours in the presence of hydrogen. The catalyst was filtered off from the reaction mixture, and the solvent in the filtrate was evaporated under reduced pressure to give the title compound (970 mg, quantitative) as a solid.

 ESI— MSmZz: 128 (M +).

 [0493] [Reference Example 72] (3S) -piperidine 3-ylcarbamic acid tert-butyl ester

 [0494] [Chemical 83]

 0

II

1) (3S) — 1 Benzylpiperidine 3-ylcarbamic acid tert butyl ester

(S) (+) —1 Benzyl-3 aminobiperidine dihydrochloride (1. Og) in N, N dimethylformamide (10 ml) at 0 ° C with potassium carbonate (1. lg) and di tert-butoxy dibonate (829 mg) was added and stirred for 30 minutes. Furthermore, it stirred at room temperature for 19.5 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to obtain (3S) -1-benzylpiperidine-3-ylcarbamic acid tert butyl ester (1. Og, 91%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.44 (9Η, s), 1.51— 1.59 (4Η, m), 2.2

 Three

 4-2.50 (4H, m), 3.47 (2H, s), 3.76 (1H, br), 4.99 (1H, br), 7.30 (5H, m).

ESI-MSm / z: 291 (M + H) ⁺ .

[0496] 2) Title compound

 To a solution of the above (3S) -1 benzylpiperidine 3-ylcarbamic acid tertbutyl ester (1. Og) in methanol (15 ml) was added 5% palladium on carbon (200 mg), and the mixture was stirred at room temperature for 20 hours in the presence of hydrogen. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure to give the title compound (663 mg, 96%) as a solid.

 'H-NMR (400MHz, CDC13) δ: 1.44 (9Η, s), 1.67—1.84 (4H, m), 2.5 3 (1H, br), 2.67 (1H, br), 2.81 (1H, br), 3.06 (1H, m), 3.57 (1H, br), 4.83 (1H, br).

ESI-MSm / z: 201 (M + H) ⁺ .

[0497] [Reference Example 73] 1— (6-Methoxy-3 pyridazil) -5 (thiazole-4-yl) 1

H-pyrazole 3-carboxylic acid

[0498] [Chemical 84]

1) 4 (thiazole-4 yl) -2, 4 dioxobutanoic acid methyl ester

In the same manner as 1) of Reference Example 4 (Method B) using 4-acetyl thiazole (3.46 g), sodium methoxide (2.94 g) and dimethyl oxalate (6.43 g) in Reference Example 64 4). 4 (Thiazole-4-yl) -2, 4 Dioxobutanoic acid methyl ester (3.67 g, 63%) Obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.94 (3H, s), 7. 42 (1H, s), 8. 34 (1H, d

 Three

 , J = 2. OHz), 8. 89 (1H, d, J = 2. OHz).

EI-MSm / z: 213 (M ⁺ ).

[0500] 2) Title compound

 In an argon atmosphere, a suspension of the above 4 (thiazole-4-yl) -2,4-dioxobutanoic acid methyl ester (3.66 g) and 3-chloro 6-hydrazinopyridazine (2.48 g) in methanol (73 ml) After heating for reflux for an hour, acetic acid (4.91 ml) was added, and the mixture was further refluxed for 69 hours. After air cooling, saturated sodium hydrogen carbonate and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black mouth form-acetone) to give 1— (6—black mouth—3 pyridazil) -5 (thiazole). 4 yl) 1H pyrazole-3-strength rubonic acid methyl ester and 1 (6-methoxy-3 pyridazil)-5 (thiazole-4 yl) — 1H pyrazole-3-carboxylic acid methyl ester mixture (4.41 g) It was. 1 1 (6 chloro-3 pyridazil) -5 (thiazole-4 yl) 1H pyrazole —3-carboxylic acid methyl ester and 1- (6-methoxy-3 pyridazil) -5 — (thiazol -4-yl) ) Sodium methoxide (2.78 g) was added at room temperature to a methanol (88 ml) suspension of a mixture of 1H-pyrazole-3-strong rubonic acid methyl ester, and heated to reflux for 85 minutes under an argon atmosphere. After air cooling, water (88 ml) was added and stirred at room temperature for 45 minutes. 1M aqueous hydrochloric acid (51.5 ml) was added to the reaction mixture and stirred, and the resulting solid was collected by filtration to give the title compound (3.88 g, 74%).

 'H-NMR (400MHz, DMSO-d) δ: 4.07 (3Η, s), 7. 32— 7. 33 (1Η, m)

 6

 , 7. 49- 7. 52 (1Η, m), 7. 97—8.00 (1Η, m), 8. 06— 8. 07 (1Η, m), 9.0

4 (1Η, m), 13. 22 (1Η, br).

 EI— MSmZz: 303 (M +).

[0501] [Reference Example 74] 1,4-Oxazepane hydrochloride

[0502] [Chemical 85]

[0503] 1) 1,4-Oxazepan 5 ON

 Under ice-cooling, azidosodium (17.8 g) was added to a concentrated hydrochloric acid (50 ml) solution of tetrahydro-4H pyran-4-one (9.80 g) over 40 minutes, followed by stirring for 30 minutes and then stirring at room temperature for 16 hours. . Under ice-cooling, sodium carbonate was added to the reaction solution to adjust the pH to 8-9, followed by liquid separation by adding black mouth form. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain 1,4-oxazepan-5-one (5.34 g, 47.4%) as a solid.

 'H-NMR (300MHz, CDC1) δ: 2. 70— 2.74 (2Η, m), 3. 32— 3. 37 (2Η,

 Three

 m), 3.75- 3.83 (4H, m), 6.31 (1H, br s).

 FAB— MSm / z: 116 (M + H) +.

[0504] 2) 1,4-Oxazepan 4

 Under an argon stream and ice-cooling, borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 40 ml) was charged with the above 1,4-oxazepan-5-one (3.041 g) over 30 minutes and stirred at room temperature for 30 minutes. did. Further, the reaction solution was heated to reflux for 2.5 hours. After air cooling, 4M hydrochloric acid dioxane solution (25 ml) and methanol (12 ml) were added to the reaction solution, and the mixture was heated to reflux for 1 hour. After cooling with air, add 1M sodium hydroxide aqueous solution (80ml) to the reaction mixture, add a solution of di-tert-butoxy carbonate (8.849g) in tetrahydrofuran (25ml) and methanol (20ml) at room temperature, and stir for 17 hours. did. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to obtain 1,4-oxazepane-4 rubonic acid tert butyl ester (2.68 g, 50%). Obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.46 (9Η, s), 1.82—1.95 (2Η, m), 3.4

 Three

 5- 3. 58 (4H, m), 3. 66— 3. 77 (4H, m).

[0505] 3) Title compound To the above solution of 1,4-oxazepane-4 rubonic acid tert butyl ester (0.468 g) in dichloromethane (9.2 ml), add 4M hydrochloric acid-dioxane solution (4.6 ml) at 0 ° C and add 0 ° C at room temperature. Stir for 5 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (0.263 g, 82%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2. 22— 2. 33 (2Η, m), 3. 27— 3. 43 (4Η,

 Three

 m), 3.82- 3.90 (2H, m), 3.92—4.01 (2H, m), 9.89 (1H, br).

ESI-MSm / z: 102 (M + H) ⁺ .

[0506] [Reference Example 75] [(1 Piperidine 2 yl) cyclopropyl] strength rubamic acid tert butyl ester

[0507] [Chemical 86]

2 シァノピリジン（3. 7[0508] 1) 2—

2 Sianopyridine (3.7

To a solution of 5 g) in tetrahydrofuran (200 ml) was added titanium black triisopropoxide (10.3 ml) at room temperature and stirred for 7 minutes. Ethylmagnesium promide (0.97M tetrahydrofuran solution, 86 ml) was added dropwise to the reaction mixture at room temperature over 5 minutes, and the mixture was stirred for 55 minutes. To the reaction solution, boron trifluoride jetyl ether complex (10.9 ml) was stirred at room temperature for 55 minutes. The reaction mixture was basified by adding 1M aqueous sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform methanol) to give 2- (1-aminocyclopropyl) pyridine (2.554 g, 53%). Obtained as an oil

ESI-MSm / z: 135 (M + H) ⁺ .

[0509] 2) [(1 Pyridine-2-yl) cyclopropyl] power rubamic acid tert butyl ester

To a solution of 2- (1-aminocyclopropyl) pyridine (513 mg) and di-tert-butyl dicarbonate (1.25 g) in dichloromethane (50 ml) at room temperature, triethylamine (1.06 ml) ) Was added and stirred for 3 days. The reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexyl monoacetate) to give [(1-pyridine-2-yl) cyclopropyl] power rubamic acid tert-butyl ester ( 563 mg, 63%) was obtained as a solid. ESI— MSm / z: 235 (M + H) +.

[0510] 3) Title compound

 Suspension of the above [(1-pyridine-2-yl) cyclopropyl] carnomic acid tert-butyl ester (277mg), 5% rhodium alumina (200mg), acetic acid (lml) and ethanol (10ml) under hydrogen atmosphere (6 atm) and stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform-methanol (10: 1) mixed solvent were added to the resulting residue for partitioning. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (297 mg, quantitative) as a solid.

ESI-MSm / z: 241 (M + H) ⁺ .

[0511] [Reference Example 76] 5- (5 Benzyloxy-2 pyridyl) -1 (6-methoxy-3-pyridyl) 1 1 H pyrazole 3 carboxylic acid

[0512] [Chemical 87]

1) 5 Benzyloxy 2 methylpyridine

3 Benzyl bromide (10.9 ml) was stirred at room temperature for 12 hours in a solution of hydroxy-6-methylpyridine (10. Og) and potassium carbonate (38.0) in acetonitrile (200 ml). Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate). Purification with 1 hexane) gave 5 benzyloxy-2-methylpyridine (4.14 g, 23%) as an oil.

 'H-NMR (400MHz, CDC1) δ: 2. 48 (3Η, s), 5. 08 (2Η, s), 7. 05 (1H, d

 Three

 , J = 8.5 Hz), 7. 16 (1H, dd, J = 8. 5, 2. 9 Hz), 7. 31—7.43 (5H, m), 8. 2 6 (1H, d, J = 2. 9Hz).

EI-MS m / z: 199 (M +).

2) 1— (5 Benzyloxy-2-pyridyl) ethanone

 Selenium dioxide (9.20 g) was added to a solution of the above 5 benzyloxy-2-methylpyridine (4.13 g) in pyridine (83 ml) at room temperature, and the mixture was heated to reflux for 61 hours. After air cooling, water and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was combined with N, O dimethylhydroxylamine hydrochloride (2.22 g), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (4.37 g). ) And 1-hydroxybenzotriazole (3.08 g) in N, N dimethylformamide (95 ml) was added triethylamine (6.35 ml) at room temperature and stirred for 61 hours. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane). 5-Benzyloxypyridine 2 carboxylic acid methoxymethylamide (3.75 g, 66% ) Was obtained as an oil. (FAB-MSmZz: 273 (M + H) +.)

 At 0 ° C under an argon atmosphere, methyl lithium (1.10 M in diethyl ether, 13.7 ml) was added to a solution of 5-benzyloxypyridine 2-strong rubonic acid methoxymethylamide (3.74 g) in tetrahydrofuran (75 ml). The solution was added dropwise and stirred for 40 minutes. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (5-benzyloxy-2-pyridyl) ethanone (1.47 g, 47%) as an oil. Obtained as a product.

 'H-NMR (400MHz, CDC1) δ: 2.67 (3Η, s), 5.18 (2Η, s), 7.30—7.45

 Three

 (6H, m), 8.03 (1H, d, J = 8.8Hz), 8.39 (1H, d, J = 2.7Hz).

EI-MS m / z: 227 (M ⁺ ). [0515] 3) 4— (5 Benzyloxy-2-pyridyl) 2, 4 Dioxobutanoic acid ethyl ester

 Under an argon atmosphere, a solution of sodium ethoxide (0.874 g) in ethanol (15 ml) and a solution of ethyl oxalate (1.75 ml) and 1 (5 benzyloxy-2-pyridyl) ethanone (1.46 g) in ethanol (15 ml) are added. The mixture was stirred at room temperature for 7 hours, and stirred at 60 ° C for 1 hour. After air cooling, sodium ethoxide (0.874 g) and decyl oxalate (1.75 ml) were further stirred at 60 ° C. for 1 hour. After air cooling, the reaction solution was washed with water using a jet ether, and then the aqueous layer was separated with a saturated salt / ammonium aqueous solution and black mouth form. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to obtain 4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (1.38 g, 66%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.38—1.42 (3Η, m), 4.35—4.42 (2Η,

 Three

 m), 5.20 (2H, s), 7.35—7.44 (6H, m), 7.59 (1H, s), 8.14 (1H, d, J = 8.8Hz), 8.44 (1H, d, J = 2.7Hz) .

EI-MSm / z: 327 (M ⁺ ).

[0516] 4) 5- (5 Benzyloxy-2-pyridyl) 1- (6-methoxy-1-pyridyl) 1H pyrazole 3-carboxylic acid ethyl ester

 To a solution of the above 41 (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ester (1.37 g) and 5-hydrazino-1-methoxypyridine (0.699 g) of Reference Example 2 in ethanol (27 ml), acetic acid (27 ml) 0.958 ml) was heated to reflux for 12 hours. After air cooling, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate hexane). 5- (5 Benzyloxy-2-pyridyl) 1- (6-methoxy-1-pyridyl) 1H pyrazole 1-Carboxylic acid ethyl ester (1.50 g, 83%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42 (3Η, t, J = 7.1Hz), 3.95 (3H, s), 4

 Three

.45 (2H, q, J = 7.1Hz), 5.10 (2H, s), 6.76 (1H, d, J = 8.8Hz), 7.18—7.42 (8H, m), 7.66 (1H, dd , J = 8.8, 2.7Hz), 8.10 (1H, d, J = 2.7Hz), 8 .28 (1H, d, J = 2.7Hz).

 FAB MSm / z: 431 (M + H) +.

[0517] 5) Title compound

 5- (5 Benzyloxy-2-pyridyl) 1- (6-methoxy-1-pyridyl) 1H-pyrazole-3-strong rubonic acid ethyl ester (1.49 g) in methanol (30 ml) and tetrahydrofuran (30 ml) at room temperature, 1 N Sodium hydroxide (8.65 ml) was stirred for 90 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was dissolved in water and chloroform, and 1M aqueous hydrochloric acid solution (8.65 ml) was added for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (1.27 g, 91%) as a solid.

'H-NMR (400MHz, CDC1) δ: 3.95 (3Η, s), 5.11 (2Η, s), 6.75— 6.78

 Three

 (1H, m), 7.22-7.41 (8H, m), 7.66 (1H, dd, J = 8.8, 2.7Hz), 8.11 (1

H, dd, J = 2.7, 0.7Hz), 8.30 (1H, dd, J = 2.7, 0.7Hz).

EI-MSm / z: 402 (M ⁺ ).

[0518] [Reference Example 77] 1— (6-Methoxy-3 pyridazil) -5— (1-methyl-1H pyrazole 1 to 4 yl) -1H-pyrazole 3 carboxylic acid

[0519] [Chemical 88]

1) 4 1 (1-methyl-1H pyrazole-4 yl) 2, 4 Dioxobutanoic acid methyl ester

Reference Example 61 3) 1- (1-methyl 1 H pyrazole 4-yl) ethanone (3.00 g) and sodium methoxide (2.61 g) are used in the same manner as 1) of Reference Example 4 Method B) 4 1 (1-methyl-1H pyrazole 4-yl) 1 2, 4 Dioxobutanoic acid methyl ester (3.48 g, 69%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 3.84 (3Η, s), 3.91 (3Η, s), 6.82 (1

 6

 H, s), 8.14 (1H, s), 8.66 (1H, s).

EI-MSm / z: 210 (M ⁺ ).

[0521] 2) 1— (6 Black-and-white 3 Pyridazil) 5— (1-Methyl 1H-pyrazole-4-yl) 1 H Pyrazole 3 Carboxylic acid methyl ester

 In an argon atmosphere, a suspension of the above 4- (1-methyl-1H pyrazole-4-yl) -2,4-dioxobutanoic acid methyl ester (3.46 g) and 3-chloro-6-hydrazinopyridazine (2.38 g) in methanol (69 ml) Was heated to reflux for 1 hour. Acetic acid (4.71 ml) was added to the reaction mixture, and the mixture was heated to reflux for 64 hours. After air cooling, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (black mouth form 1-acetone). 1— (6 black mouth 3 pyridazil) —5— (1— Methyl 1H pyrazol 4-yl) -1H pyrazole-3-carboxylic acid methyl ester (4.30 g, 82%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.94 (3Η, s), 3.99 (3Η, s), 7.03 (1H, s)

 Three

 , 7.64 (1H, s), 7.68-7.70 (1H, m), 7.96 (1H, s), 8.07-8.10 (1H, m).

EI-MSm / z: 318 (M ⁺ ).

[0522] 3) Title compound

1 ( ₆ Chloro-pyridazil) -methyl-1 under argon atmosphere

1 H pyrazole-4-yl) To a suspension of 1H pyrazole-3-carboxylic acid methyl ester (4.29 g) in methanol (86 ml), sodium methoxide (2.18 g) was heated at reflux at room temperature for 4 hours. After air cooling, water (86 ml) was added and stirred for 1 hour. A 1M aqueous hydrochloric acid solution (40.4 ml) was added to the reaction solution and stirred, and the resulting solid was collected by filtration to obtain the title compound (3.35 g, 83%).

 'H-NMR (400MHz, DMSO-d) δ: 3.81 (3Η, s), 4.12 (3Η, s), 7.07 (1

 6

Η, s), 7.48 (1Η, s), 7.52 (1H, d, J = 9.3Hz), 7.78 (1H, s), 7.95 (1H, d , J = 9.3Hz), 13.10 (1H, br).

EI-MSm / z: 300 (M ⁺ ).

[0523] [Example 1] 4— [5— (5-Methoxy-2-pyridyl) 1- (6-methyl-3-pyridyl)

1H-pyrazole 3 carbo] morpholine

[0524] [Chemical 89]

[0525] Reference Example 9 5— (5-Methoxy-2-pyridyl) 1— (6-Methyl-3-pyridyl) 1H —Pyrazole-3-carboxylic acid (0.200 g), 3— (3 dimethylaminopropyl) — 1— Ethylcarbodiimide hydrochloride (0.136 g) and 1-hydroxybenzotriazole (95.8 mg) in N, N-dimethylformamide (4 ml) solution with morpholine (84.2 1) and triethylamine (98.8 1) at room temperature 14 Stir for hours. Water and chloroform were separated into the reaction solution, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform form) to obtain the title compound (0.186 g, 76%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.59 (3Η, s), 3.73—3.84 (6Η, m), 3.8

 Three

 7 (3H, s), 4.14 (2H, m), 7.07 (1H, s), 7.18— 7.22 (2H, m), 7.37 (1H, d, J = 8.5Hz), 7.59-7.62 (1H, m), 8.19 (1H, d, J = 2.9Hz), 8.39 (1H, d, J = 2.4Hz).

 EI-MSm / z: 379 (M +).

 Elemental analysis: as C H N O

 20 21 5 3

 Theoretical values: C, 63.31; H, 5.58; N, 18.46.

 Found: C, 63.42; H, 5.62; N, 18.51.

[0526] [Example 2] 1— [5 -— (5-Methyl-2-pyriduryl) —1— (6-Methyl-3-pyridyl)

1H Pyrazole-3 Carbonyl] —4,4-Difluoropiperidine [0527] [Chemical 90]

[0528] Reference Example 8 5— (5-Methyl-2-virazil) —1— (6-Methyl-3-pyridyl) -1 H pyrazole-3-carboxylic acid (0.228 g) and Reference Example 4, 4, The title compound (0.252 g, 82%) was obtained as a solid in the same manner as in Example 1 using 4 difluoropiveridine hydrochloride (0.146 g).

 'H-NMR (400MHz, CDC1) δ: 2.10 (4Η, m), 2.58 (3Η, s), 2.61 (3H, s

 Three

 ), 3.93 (2H, m), 4.20 (2H, m), 7.22— 7.24 (2H, m), 7.61— 7.63 (1H

, m), 8.34 (1H, m), 8.41 (1H, d, J = 2.4Hz), 8.61 (1H, d, J = l.5Hz).

EI— MSmZz: 398 (M +).

[0529] [Example 3] 1— [5 -— (5-Methyl-2-pyriduryl) —1— (6-Methyl-3-pyridyl)

 1H pyrazole-3 carbonyl] -4-methoxypiperidine

[0530] [Chem 91]

参考例 8の 5—（5—メチルー 2—ビラジ-ル）ー1 （6—メチルー 3 ピリジル）ー1 H ピラゾールー 3—力ルボン酸（0.228g)と参考例 23の 4ーメトキシピペリジン塩 酸塩 (0. 142g)とを用いて、実施例 1と同様の方法で標題ィ匕合物（0.244g, 80%) を固体として得た。

5- (5-Methyl-2-virazil) -1 (6-methyl-3-pyridyl) -1 H pyrazole-3-strong rubonic acid (0.228 g) of Reference Example 8 and 4-methoxypiperidine hydrochloride of Reference Example 23 (0.142 g) was used in the same manner as in Example 1 to obtain the title compound (0.244 g, 80%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.69 (2Η, m), 1.95 (2Η, m), 2.58 (3H,

 Three

s), 2.61 (3H, s), 3.38-3.39 (3H, m), 3.48—3.58 (2H, m), 3.74— 3. 78 (IH, m), 4.09 (1H, m), 4.28 (IH, m), 7.18 (1H, s), 7.22 (1H, d, J =

8.3Hz), 7.62-7.65 (1H, m), 8.34 (1H, s), 8.41 (IH, d, J = 2.4Hz), 8

.61 (IH, s).

EI-MSm / z: 392 (M ⁺ ).

[0532] [Example 4] 1— [5— (5-Methoxy-1-pyridyl) 1- (6-methyl-3-pyridyl)

1H-pyrazole 3 carbonyl] 4-methoxypiperidine

[0533] [Chem 92]

[0534] 5-(5-Methoxy-2-pyridyl) 1- (6-methyl-3-pyridyl) 1H-pyrazole-3-strong rubonic acid (0.200 g) and 4-methoxypiperidine hydrochloride of Reference Example 23 (0 119 g) to give the title compound (0.208 g, 79%) as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDCl) δ: 1.68 (2Η, m), 1.94 (2Η, m), 2.59 (3H,

 Three

 s), 3.38 (3H, s), 3.47-3.55 (2H, m), 3.68— 3.76 (IH, m), 3.87 (3H, s), 4.09 (IH, m),

 4.25 (1H, m), 7.00 (1H, s), 7.17— 7.21 (2H, m), 7.36— 7.38 (1H, m), 7.62 (1H, dd, J = 8.3, 2.7Hz), 8.19 (1H, d, J = 2.9Hz), 8.39 (1H, d, J = 2.7Hz).

EI-MSm / z: 407 (M ⁺ ).

 Elemental analysis: as C H N O

 22 25 5 3

 Theoretical values: C, 64.85; H, 6. 18; N, 17.19.

 Found: C, 64.85; H, 6.09; N, 17.28.

[0535] [Example 5] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H pyrazole 3-carbol] hexahydropyridazine [0536] [Chemical 93]

[0537] Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo One-Lou 3-Strong Rubonic Acid (0.610 g) in dichloromethane (20 ml) at room temperature (3-Dimethylaminopropyl) 1-ethylcarbodiimide hydrochloride (0.864 g), 1-hydroxybenzotriazole (0.309 g), triethylamine (1.20 ml) and hexahydropyridazine hydrochloride of Reference Example 20 (0.292 g) Was added and stirred for 21 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethanol monochloroform) to obtain the title compound (0.360 g, 48%) as a solid. 'H-NMR (400MHz, CDC1) δ: 1.67—1.87 (4Η, m), 2.96—3.07 (2Η,

 Three

 m), 3.85 (2HXl / 3, br), 4.11 (3H, s), 4.23 (2HX2 / 3, br), 6.66 (1H

Xl / 3, s), 7. 10-7.27 (3H, m), 7. 10— 7.27 (lHX2 / 3, m), 7.51— 7

.62 (1H, m), 7.65—7.82 (2H, m), 8.41 (1H, br).

 ESI— MSm / z: 366 (M + H) +.

[0538] [Example 6] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H pyrazole 3 carbonyl] 2-methylpyrazolidine

[0539] [Chemical 94]

[0540] 1) 2— [1— (6-Methoxy-1-pyridazil) 5— (2 Pyridyl) 1H-Vilazo '

3 CARBOL] PYRAZOLIDINE Reference Example 1 1- (6-Methoxy-3 pyridazil) -5- (2 pyridyl) -1H pyrazole 3 carboxylic acid (1.003 g) and pyrazolidine 1 carboxylic acid tert-butyl ester (0.910 g, Y. Endo et al., Bioorg. Med. Chem., 2002, 10, 953) and 2— [1 (6-methoxy-3-pyridazil) -5- (2 pyridyl) 1H in the same manner as in Example 5. Pyrazole 3 carbonyl] pyrazolidine 1 carboxylic acid tert-butyl ester (1.31 g, 86%) was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 1.40 (9Η, br s), 2.05—2.22 (2H, br),

 Three

 3. 15-3.60 (2H, br), 4.05—4.35 (2H, br), 4.09 (3H, s), 7.12 (1H, d, J = 9.3Hz), 7.15-7.25 (2H, m), 7.55 ( 1H, br d, J = 7.8Hz), 7.73 (1H, dt, J = 7.8, 1.7Hz), 7.90—8.00 (1H, br), 8.41 (1H, brd, J = 4.1Hz) .FAB MSm / z : 452 (M + H) +.

2) 1- (6-Methoxy-1-pyridazil) 5- (2 Pyridyl) 1H Pyrazole 3-Carboyl] virazolidine

 2— [1— (6 Methoxy 3 pyridazil) 5 — (2 pyridyl) 1H pyrazole — 3 carbol] pyrazolidine — 1 Carboxylic acid tert -butyl ester (1.31 g) in dichloromethane (30 ml) at room temperature A 4N hydrochloric acid-dioxane solution (10 ml) was added and stirred for 1 hour. Jetyl ether was added to the reaction solution, and the precipitated solid was collected by filtration. To this solid, black mouth form and saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol monochloroform). 1- [1- (6-Methoxy-1-pyridazil) 5- (2pyridyl) ) 1H Pyrazole 1-carbol] virazolidine (0.591 g, 59%) was obtained as a solid.

'H-NMR (400MHz, CDC1) δ: 2.05— 2.30 (2Η, m), 3.11— 3.26 (2Η,

 Three

m), 3.75-3.86 (1H, m), 4.10 (3H, s), 4.12—4.20 (1H, m), 4.60—4.70 (lHX2 / 3, br), 5.45—5.53 (lHXl / 3 , br), 7.11 (1ΗΧ2 / 3, s), 7.13 (lHXl / 3, s), 7.16-7.34 (2H, m), 7.52—7.96 (3H, m), 8.35—8.45 (1H, br).

ESI-MSm / z: 352 (M + H) ⁺ . [0542] 3) Title compound

 1— [1— (6 Methoxy 3 pyridazil) 5 — (2 Pyridyl) -1H-pyrazole —3-Carbol] virazolidine (0.419 g) in N, N dimethylformamide (8. Oml) solution 0 Sodium hydride (55% in oil, 63.6 mg) was added at ° C and stirred for 20 minutes. Methyl iodide (0.11 lml) was added to the reaction solution and stirred for 1 hour. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol monochloroform) to obtain the title compound (0.190 g, 59%) as a solid. 'H-NMR (400MHz, CDC1) δ: 1.95— 2.33 (2Η, br), 2.65 (3ΗΧ2 / 3,

Three

 br s), 2.75 (3HXl / 3, brs), 3.02— 3.18 (2H, m), 3.80— 3.95 (2HX2 / 3, br), 4.09 (3H, s), 4.15—4.25 (2HXl / 3, br) , 7.10-7.40 (3H, m), 7.52-7.80 (2H, m), 7.74 (lHX2 / 3, d, J = 7.3Hz), 8.35-8.50 (1 H, br).

 ESI— MSm / z: 366 (M + H) +.

[0543] [Example 7] 1- [1 (6-Methoxy-3 pyridyl) -5- (2 pyridyl) 1H pyrazole- 3-carbol] -2-formylpyrazolidine

[0544] [Chemical 95]

1) 1— [1— (6-Methoxy-1-pyridyl) -5- (2 pyridyl) 1H pyrazole-3 carbo] pyrazolidine 1 carboxylic acid tert butyl ester

Reference Example 1 1- (6-Methoxy-3-pyridyl) 5- (2 Pyridyl) 1H Pyrazolu 3 Carboxylic acid (1.073 g) and Virazolidine 1 Carboxylic acid tert-Butyl ester (0.967 g, Y. Endo et al., Bioorg Med. Chem., 2002, 10, 953) in the same manner as Example 5 2- [1— (6-Methoxy-3 pyridyl) -5- (2 pyridyl) -1 H-pyrazole 3 carbo] pyrazolidine 1 carboxylic acid tert-butyl ester (1.33 g, 82%) was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 1.41 (9Η, br s), 2.05— 2.20 (2H, m),

 Three

 3. 15-3.60 (2H, br), 3.94 (3H, s), 4.00—4.50 (2H, br), 6.74 (1H, d, J = 8.7Hz), 7.15-7.43 (3H, m), 7.64 ( 1H, dd, J = 8.7, 2.7Hz), 7.67 (1H, dt, J = 7.8, 1.5Hz), 8.09 (1H, d like, J = l.5Hz), 8.50 (1H, d like, J = 4.9 Hz).

 FAB MSm / z: 451 (M + H) +.

[0546] 2) 1— [1— (6-Methoxy-1-pyridyl) 5-- (2 Pyridyl) 1H Pyrazole 1-3 Carbo] razolidine

 2— [1— (6-Methoxy-1-pyridyl) 5— (2 Pyridyl) 1H Pyrazole-3-carbol] pyrazolidine-1 Carboxylic acid tert-butyl ester (1.33 g) In the same manner, 1 [1- (6-methoxy-3-pyridyl) -5- (2 pyridyl) 1H pyrazole-3 carbo] virazolidine (0.895 g, 87%) was obtained as an amorphous.

 'H-NMR (400MHz, CDC1) δ: 2.08— 2.30 (2Η, m), 3.10— 3.25 (2Η,

 Three

 m), 3.76-3.81 (2HX2 / 3, m), 3.95 (3H, s), 4.10—4.23 (2HXl / 3, m), 4.76 (lHX2 / 3, br), 5.46 (lHXl / 3, br), 6.75 (1H, d like, J = 8.8Hz), 7.17-7.76 (5H, m), 8.13 (1H, d like, J = 2.2Hz), 8.50 (1H, br).

 FAB MSm / z: 351 (M + H) +.

[0547] 3) Title compound

1— [1— (6 Methoxy 3 pyridinole) 5 — (2 Pyridinole) -1H-pyrazolone 1 —Carboyl] virazolidine (0.306 g) in N, N dimethylformamide (5. Oml) solution at 0 ° C 4- (dimethylamino) pyridine (0.212 g) and trifluoromethanesulfonic anhydride (0.220 ml) were added and stirred for 1 hour. A sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. (1) methanol (chloroform form) to give the title compound (0.196 g, 59%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.13— 2.25 (2Η, m), 3.66— 3.77 (2Η,

 Three

 m), 3.95 (3H, s), 4.07—4.18 (2H, br), 6.76 (1H, d, J = 9. OHz), 7.23 -7.34 (2H, m), 7.41 (1H, d, J = 7.8 Hz), 7.60 (1H, dd, J = 9.0, 2.7Hz),

 7.72 (1H, dt, J = 7.8, 2. OHz), 8.10 (1H, d, J = 2. OHz), 8.52 (1H, br d, J = 4.9Hz), 8.59 (1H, br s) .ESI — MSm / z: 379 (M + H) +.

 Elemental analysis: C H N O · 0.25H O

 19 18 6 3 2

 Theoretical values: C, 59.60; H, 4.87; N, 21.95.

 Found: C, 59.52; H, 4.77; N, 21.85.

 [0548] [Example 8] 1- [1 (6-Methoxy-3-pyridyl) -5- (2 pyridyl) 1H pyrazole 3-carbonyl] -2-methanesulfol pyrazolidine

[0549] [Chemical 96]

ivieu

[0550] In (7-methoxy-3 pyridyl) -5- (2 pyridyl) 1H-pyrazole-3carbol] virazolidine (0.282 g) in Example 7 2) in dichloromethane (5. Oml) at room temperature Triethylamine (0.168 ml) and methanesulfonyl chloride (0.0749 ml) were added and stirred for 3 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform form) to obtain the title compound (0.230 g, 67%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.22— 2.36 (2Η, m), 3.19 (3Η, s), 3.7

 Three

5 (2H, br), 3.96 (3H, s), 4.28 (2H, br), 6.77 (1H, d, J = 8.8Hz), 7.21 -7.28 (IH, m), 7.30 (1H, s), 7.41 (IH, d like, J = 7.8Hz), 7.61 (IH, dd, J = 8.8, 2.7Hz), 7.71 (IH, dt, J = 7.8, 1.7Hz), 8.12 (1H, d, J = 2.7Hz), 8.52 (IH, d like, J = 4.9Hz).

ESI-MSm / z: 429 (M + H) ⁺ .

 Elemental analysis: as C H N O S

 19 20 6 4

 Theoretical values: C, 53.26; H, 4.70; N, 19.61; S, 7.48.

 Found: C, 53.19; H, 4.68; N, 19.48; S, 7.51.

 [0551] [Example 9] 1 [1 (6-methoxy-3-pyridazil) 5- (2 pyrajuryl) 1H-pyrazole 3-carbonyl] 4, 4 difluoropiperidine

[0552] [Chemical 97]

 [0553] Reference Example 12-1 (6-Methoxy-3-pyridazil) -5- (2 Pyradur) 1H Pyrazole-3-carboxylic acid (0.232 g) and Reference Example 18, 4, 4 Difluoropiperidine Hydrochloride (0.222 g) was used to give the title compound (0.265 g, 84%) as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 2.06— 2.14 (4Η, m), 3.92— 3.96 (2Η,

 Three

 m), 4.12 (3H, s), 4.14—4.18 (2H, m), 7.19 (1H, d, J = 9.3Hz), 7.23 (IH, s), 7.85 (1H, d, J = 9.3Hz ), 8.42- 8.43 (1H, m), 8.53 (IH, d, J = 2.4Hz), 8.83-8.84 (1H, m).

 ESI MSm / z: 402 (M + H) +.

 Elemental analysis: as C H FN O

 18 17 2 7 2

 Theoretical values: C, 53.86; H, 4.27; N, 24.43; F, 9.47.

 Found: C, 53.57; H, 4.22; N, 24.39; F, 9.17.

[0554] [Example 10] 1— [1— (6-Methoxy-3-pyridyl) -5- (1H-pyrrole 1 yl) — 1H pyrazole 3 carbonyl] 4 methyl 3-oxopiperazine

[0555] [Chemical 98]

[0556] 1- (6-Methoxy-1-pyridyl) 5-(1H pyrrole-1-yl) 1 H pyrazole 3 carboxylic acid (0.22 lg) and 1-methylbiperazine 2-one hydrochloride of Reference Example 21 (Reference Example 11) In the same manner as in Example 1, the title compound (0.239 g, 80%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 3.03 (3Η, s), 3.45—3.52 (2Η, m), 3.9

 Three

 5 (3H, s), 4.03-4.06 (1H, m), 4.42—4.46 (2H, m), 4.83 (1H, br s), 6.31 (2H, t, J = 2.1 Hz), 6.66 (2H, t, J = 2.2Hz), 6.71 (1 / 2H, s), 6.7 3 (1 / 2H, s), 6.86 (1 / 2H, br s), 6.91 (1 / 2H, br s), 7.18— 7.23 (1 / 2H, m), 7.32-7.35 (1 / 2H, m), 7.96—7.98 (1 / 2H, m), 8.05—8.07 (1 / 2H, m).

ESI-MSm / z: 381 (M + H) ⁺ .

 Elemental analysis: as C H N O

 19 20 6 3

 Theoretical values: C, 59.99; H, 5.30; N, 22.09.

 Found: C, 59.97; H, 5.23; N, 22.23.

 [0557] [Example 11] 1— [1— (6-Methoxy-3-pyridyl) -5- (1H-pyrrole 2 yl)

 -1H-pyrazole 3 carbonyl] 4 methyl 3oxopiperazine

[0558] [Chemical 99]

[0559] 参考例 5の 1— (6—メトキシ— 3 ピリジル）—5— (1H ピロール— 2—ィル） 1 H ピラゾールー 3—力ルボン酸（0.222g)と参考例 21の 1ーメチルビペラジン 2 —オン塩酸塩 (0.212g)とを用いて、実施例 1と同様の方法で標題ィ匕合物（0.246 g, 82%)を固体として得た。

[0559] 1- (6-Methoxy-3-pyridyl) -5- (1H pyrrole-2-yl) 1 H pyrazole- 3-strength rubonic acid (0.222 g) and Reference Example 21 The title compound (0.246 g, 82%) was obtained as a solid in the same manner as in Example 1 using perazin 2-one hydrochloride (0.212 g).

 'H-NMR (400MHz, DMSO-d) δ: 2.87 (3Η, s), 3.38—3.42 (2Η, m)

 6

 , 3.89 (1Η, br s), 3.93 (3H, s), 4.18 (1H, br s), 4.25—4.28 (1H, m), 4.67 (1H, br s), 5.54 (1H, br s), 5.99 — 6.01 (1H, m), 6.88— 6.90 (1H, m), 6.97-7.04 (2H, m), 7.81 (1H, dd, J = 8.8, 2.7Hz), 8.27— 8.30 (1H, m) , 11.42 (1H, br s).

ESI-MSm / z: 381 (M + H) ⁺ .

 [0560] [Example 12] 1— [1— (6-Methoxy-3-pyridazil) 5— (1H—pyrrole-2-yl) 1H pyrazole-3 carbol] -4-methylbiperazine

 [0561] [Chemical 100]

参考例 10の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (1H ピロール— 2—ィル )— 1H ピラゾールー 3—カルボン酸（0.222g)と N—メチルビペラジン（0.156ml )とを用いて、実施例 1と同様の方法で標題ィ匕合物（0.197g, 68%)を固体として得 た。

Using Reference Example 10 1- (6-Methoxy-3 pyridazil) -5- (1H pyrrole-2-yl) -1H pyrazole-3-carboxylic acid (0.222 g) and N-methylbiperazine (0.156 ml) In the same manner as in Example 1, the title compound (0.197 g, 68%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.33 (3Η, s), 2.42— 2.45 (2Η, m), 2.4

 Three

 9-2.52 (2H, m), 3.83— 3.86 (2H, m), 3.94— 3.97 (2H, m), 4.19 (3H, s), 6.28-6.31 (1H, m), 6.61— 6.64 (1H, m ), 6.94 (1H, s), 6.96— 6.98 (1H, m), 7.19 (1H, d, J = 9.3Hz), 8.00 (1H, d, J = 9.5Hz), 11.56 (1H, br s ).

ESI— MSm / z: 368 (M + H) +. Elemental analysis: as CHNO

 18 21 7 2

 Theoretical values: C, 58.84; H, 5.76; N, 26.69.

 Found: C, 58.54; H, 5.71; N, 26.82.

[0563] [Example 13] 4- [1- (6-Methoxy-3-pyridyl) -5- (1H-pyrrole 1 yl)

 -1H pyrazole-3-carbol] morpholine

[0564] [Chemical 101]

[0565] 1- (6-Methoxy-3pyridyl) -5- (1H pyrrole-1 yl) of Reference Example 11 Using 1 H pyrazole mono-3-carboxylic acid (0.221 g) and morpholine (0.123 ml) In the same manner as in Example 1, the title compound (0.227 g, 82%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.74— 3.84 (6Η, m), 3.94 (3Η, s), 4.1

 Three

 7-4.20 (2H, m), 6.29— 6.31 (2H, m), 6.66— 6.67 (2H, m), 6.71 (1H

, d, J = 8.8Hz), 6.86 (1H, s), 7.25 (1H, dd, J = 8.8, 2.7Hz), 8.02 (1H

, d, J = 2.9Hz).

 ESI MSm / z: 354 (M + H) +.

 Elemental analysis: as C H N O

 18 19 5 3

 Theoretical values: C, 61.18; H, 5.42; N, 19.82.

 Found: C, 61.23; H, 5.46; N, 19.70.

 [Example 14] 1 [1- (6-Methoxy-3-pyridazil) 5- (1H-pyrrole 2-yl) -1H pyrazole-3-carbol] -4-methoxypiperidine

[0566] [Chemical 102]

[0567] Reference Example 10-1 (6-methoxy-3-pyridazil) -5- (1H-pyrrole-2-yl) -1H pyrazole-3-carboxylic acid (0.222 g) and 4-methoxypiveridi of Reference Example 23 In the same manner as in Example 1, the title compound (0.177 g, 59%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.61— 1.75 (2Η, m), 1.86— 2.00 (2Η,

Three

 m), 3.38 (3H, s), 3.47— 3.65 (3H, m), 4.05—4.16 (2H, m), 4.19 (3H, s), 6.28-6.31 (1H, m), 6.61— 6.64 (1H, m), 6.91 (1H, s), 6.96— 6.98 (1H, m), 7.18 (1H, d, J = 9.5Hz), 8.01 (1H, d, J = 9.3Hz), 11.60 (1H, br s).

 ESI— MSm / z: 383 (M + H) +.

 Elemental analysis: as C H N O

 19 22 6 3

 Theoretical values: C, 59.67; H, 5.80; N, 21.98.

 Found: C, 59.44; H, 5.74; N, 22.03.

[0568] [Example 15] 4- [1- (6-Methoxy-3 pyridazil) -5- (1H-pyrrole-2-yl) 1H pyrazole-3 carbol] morpholine

[0569] [Chemical 103]

Using Reference Example 10 1- (6-Methoxy-3 pyridazil) -5- (1H pyrrole-2-yl) -1H pyrazole mono 3-carboxylic acid (0.222 g) and morpholine (0.123 ml) In the same manner as in Example 1, the title compound (0.197 g, 68%) was obtained as a solid. NMR-NMR (400MHz, CDCl) δ: 3.70— 3.73 (2H, m), 3.79— 3.84 (4H,

 Three

 m), 4.00-4.03 (2H, m), 4.20 (3H, s), 6.29—6.31 (1H, m), 6.62— 6

.64 (1H, m), 6.96— 6.98 (2H, m), 7.20 (1H, d, J = 9.5Hz), 7.97 (1H, d, J = 9.5Hz), 11.53 (1H, br s).

 ESI— MSm / z: 355 (M + H) +.

[Example 16] 4- [1— (6-Methyl-3 pyridyl) -5- (1-methyl-1H pyrrole

 -3 il) -1H-pyrazole 3 carbo] morpholine

[0572] [Chemical 104]

[0573] 1 of Reference Example 14 (6-Methyl-3-pyridyl) -5- (1-Methyl- 1H-Pyrroyl 3-Ill)-1H Pyrazole mono-carboxylic acid (0.260 g) and morpholine (0.200 ml) Was used to obtain the title compound (0.228 g, 71%) as a solid in the same manner as in Example 5.

'H-NMR (400MHz, CDCl) δ: 2.62 (3Η, s), 3.60 (3Η, s), 3.67— 3.86

 Three

 (6H, m), 4.10-4.20 (2H, m), 5.86— 5.90 (1H, m), 6.47— 6.53 (2H, m), 6.79 (1H, s), 7.21 (1H, d, J = 8.1 Hz ), 7.64 (1H, dd, J = 8.1, 2.7H z), 8.57 (1H, d, J = 2.7Hz).

ESI-MSm / z: 352 (M + H) ⁺ .

[0574] [Example 17] 1— [1- (6 Hydroxy 3 pyridazil) 5— (2 Pyridyl) 1H Pyrazole 3-carbonyl] 4 Methylbiperazine

[0575] [Chemical 105]

[0576] 1) 1— (6 Hydroxy-3-pyridazil) 5— (2 Pyridyl) 1H Pyrazole 3- 3-Strength Rubonic Hydrochloride

 Reference Example 4 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) -1H Pyrazo 1-Lu 3-Strength rubonic acid (0.60 g) in 1N hydrochloric acid (12 ml) heated to reflux for 4 hours did. After air cooling, the solvent of the reaction solution was distilled off under reduced pressure to obtain 1 (6 hydroxy-3 pyridazinyl) 5- (2 pyridyl) 1H pyrazole-3-strong rubonic acid hydrochloride (0.641 g, 96%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 7.04— 7.06 (1Η, m), 7.37— 7.40 (

 6

 2H, m), 7.70 (1H, d, J = 9.8Hz), 7.86— 7.95 (2H, m), 8.49 (1H, d, J = 4.6Hz), 13.01 (1H, br s).

 EI— MSmZz: 283 (M +).

[0577] 2) Title compound

 1- (6 Hydroxy-3-pyridazyl) 5-- (2 Pyridyl) 1H Pyrazole 1-3-Carboxylic acid hydrochloride (0.250 g) and N-methylbiperazine (0.104 ml) were used in the same way as Example 1. The method yielded the title compound (0.149 g, 50%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.33 (3Η, s), 2.45—2.52 (4Η, m), 3.8

 Three

 1 (2H, m), 4.04 (2H, m), 7.04 (1H, d, J = 10.0Hz), 7.10 (1H, s), 7.24

-7.27 (1H, m), 7.58-7.62 (2H, m), 7.75-7.79 (1H, m), 8.47-8.

48 (1H, m), 11.23 (1H, br s).

 EI— MSmZz: 365 (M +).

[0578] [Example 18] 1— [1— (6-Methyl-3-pyridazil) -5- (5-methyl-2-pyridyl) 1H-pyrazole-3 carbol] —4,4-difluoropiperidine

[0579] [Chem 106]

[0580] Reference Example 15 1- (6-Methyl-3 pyridazil) -5- (5-Methyl-2-pyridyl) — 1H Pyrazole-3-carboxylic acid (0.250 g) and Reference Example 18, 4, 4 difluoropiperidine The title compound (0.236 g, 70%) was obtained as a solid in the same manner as in Example 1 using hydrochloride (0.160 g).

 'H-NMR (400MHz, CDC1) δ: 2.09— 2.10 (4Η, m), 2.33 (3Η, s), 2.7

 Three

 4 (3H, s), 3.92-3.94 (2H, m), 4.15—4.17 (2H, m), 7.08 (1H, s), 7. 47-7.57 (3H, m), 7.82 (1H, d , J = 8.8Hz), 8.23 (1H, m).

 EI— MSmZz: 398 (M +).

 Elemental analysis: as C H F N O

 20 20 2 6

 Theoretical values: C, 60.29; H, 5.06; N, 21.09; F, 9.54.

 Found: C, 60.11; H, 4.97; N, 20.95; F, 9.40.

 [0581] [Example 19] 1 [1- (6-Methoxy-3-pyridazil) 5- (2 pyridyl) 1H-pyrazole 3-carbonyl] 4 Methylbiperidine

[0582] [Chemical 107]

参考例 4の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (2 ピリジル）—1H ピラゾ 一ルー 3—カルボン酸（0.250g)と 4ーメチルビペリジン（0. 119ml)とを用いて、実 施例 1と同様の方法で標題ィ匕合物（0.289g, 90%)を固体として得た。

Reference Example 1 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) -1H Pyrazo 1-lu 3-Carboxylic acid (0.250 g) and 4-methylbiperidine (0.119 ml) The title compound (0.289 g, 90%) was obtained as a solid in the same manner as in Example 1.

'H-NMR (400MHz, CDC1) δ: 0.98 (3Η, d, J = 6.1Hz), 1.19— 1.28 (2 H, m), 1.60-1.76 (3H, m), 2.76— 2.84 (1H, m), 3. 11— 3.17 (1H, m

), 4.10 (3H, s), 4.62-4.74 (2H, m), 7.04 (IH, s), 7.12—7.14 (1H, m), 7.20-7.24 (IH, m), 7.56—7.58 (1H) , m), 7.72—7.76 (IH, m), 7

.83 (1H, d, J = 9.3Hz), 8.41—8.43 (1H, m).

 EI-MSm / z: 378 (M +).

Elemental analysis: C H N O · 0.25H O

 20 22 6 2 2

Theoretical value: C, 62.73; H, 5.92; N, 21.95.

Found: C, 62.92; H, 5.79; N, 21.97.

 [Example 20] 1— [1— (6-Methoxy-3-pyridyl) 5- (2 pyridyl) 1H virazole 3-carbonyl] 4-methoxypiperidine

[Chemical 108]

参考例 3の 1— (6—メトキシ一 3 ピリジル） 5— (2 ピリジル） 1H ピラゾー ルー 3—カルボン酸（0.250g)と参考例 23の 4—メトキシピぺリジン塩酸塩（0.142g )とを用いて、実施例 1と同様の方法で標題ィ匕合物（0.302g, 90%)を固体として得 た。

Using Reference Example 3 1- (6-Methoxy-1-pyridyl) 5- (2 Pyridyl) 1H Pyrazolu 3-carboxylic acid (0.250 g) and Reference Example 23 4-methoxypiperidine hydrochloride (0.142 g) In the same manner as in Example 1, the title compound (0.302 g, 90%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.67 (2Η, m), 1.94 (2Η, m), 3.37 (3H,

 Three

s), 3.47-3.55 (2H, m), 3.71—3.76 (IH, m), 3.95 (3H, s), 4.09 (IH

, m), 4.27 (1H, m), 6.75 (IH, d, J = 8.8Hz), 7.09 (1H, s), 7.21—7.2

5 (1H, m), 7.40-7.42 (1H, m), 7.59 (1H, dd, J = 8.8, 2.7Hz), 7.68—

7.72 (1H, m), 8.11 (1H, d, J = 2.7Hz), 8.51-8.53 (1H, m).

 EI— MSmZz: 393 (M +).

Elemental analysis: C H N O · 0.25H O

 21 23 5 3 2

Theoretical values: C, 63.38; H, 5.95; N, 17.60. Found: C, 63.53; H, 5.83; N, 17.69.

[0586] [Example 21] (3R) — 1— [1— (6-Methoxy-3 pyridyl) -5- (2 pyridyl) -1

H pyrazole 3-carbonyl] 3-fluoropiperidine

[0587] [Chem 109]

[0588] Reference Example 3 1- (6-Methoxy-1-pyridyl) 5-(2 Pyridyl) 1H Pyrazol Nore 3 Power Norebonic acid (318 mg) and Reference Example 26 (3R) -3 fluoropiperidine hydrochloride (150 mg) was used to obtain the title compound (271 mg, 66%) as a solid in the same manner as in Example 5.

 'H-NMR (400MHz, CDCl) δ: 1.59 (1Η, br s), 2.00 (3Η, br s), 3.53

 Three

 (0.5H, s), 3.93-4.13 (6H, m), 4.33 (0.5H, s), 4.70 (1H, d, J = 46.6 Hz), 6.76 (1H, d, J = 8.8Hz), 7.13 ( 1H, s), 7.22— 7.26 (1H, m), 7.47 (1H, d, J = 8. OHz), 7.56 (1H, d, J = 32. OHz), 7.71 (1H, td, J = 7.8, 1.2Hz), 8.12 (1H, d, J = 2.4Hz), 8.52 (1H, d, J = 4.9Hz).

ESI-MSm / z: 382 (M + H) ⁺ .

 Elemental analysis: as C H FN O

 20 20 5 2

 Theoretical values: C, 62.98; H, 5.29; N, 18.36.

 Found: C, 62.70; H, 5.22; N, 18.12.

 [0589] [Example 22] (3R) — 1— [1— (6-Methoxy-3 pyridazil) -5- (2 pyridyl)

 -1H-pyrazole 3 carbonyl] 3 fluoropiperidine

[0590] [Chem 110]

[0591] Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo One-Lou 3-Strength Rubonic Acid (297 mg) and Reference Example 26 (3R) — 3 Fluoro The title compound (268 mg, 70%) was obtained as a solid in the same manner as in Example 5 using piperidine hydrochloride (140 mg).

 'H-NMR (400MHz, CDC1) δ: 1.64 (1Η, br s), 2.00 (3Η, br s), 3.50

 Three

 —4.30 (4H, m), 4.10 (3H, s), 4.72 (1H, dd, J = 46.1, 25.1Hz), 7.10

-7. 15 (2H, m), 7.20— 7.23 (1H, m), 7.59 (1H, br s), 7.72— 7.85 (2

H, m), 8.40-8.42 (1H, m).

 ESI— MSm / z: 383 (M + H) +.

[0592] [Example 23] (2S) -1 [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl)

 -1H Pyrazole 3-Carbonyl] — 2 Trifluoromethylpyrrolidine

[0593] [Chem 111]

[0594] Reference Example 1 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl)

1 3 Carboxylic acid (378 mg) and (2S) — 2

 Was used to obtain the title compound (240 mg, 45%) as a solid in the same manner as in Example 5.

H—NMR (400MHz, CDC1) δ: 2.05— 2.25 (4Η, m), 3.72—6.05 (3Η,

 Three

m), 4.11 (3H, s), 7.14 (1H, d, J = 9.0Hz), 7.20— 7.30 (2H, m), 7.57 (1H, br s), 7.62-7.81 (2H, m), 8.40 (1H, d, J = 4.6Hz). ESI-MSm / z: 419 (M + H) ⁺ .

 Elemental analysis: as C H FN O

 19 17 3 6 2

 Theoretical values: C, 54.55; H, 4. 10; N, 20.09.

 Found: C, 54.32; H, 4.04; N, 20.05.

 [Example 24] (33) -1 [1- (6-Methoxy-3-pyridyl) 5- (2 pyridyl) 1 H pyrazole 3-carbonyl] 3-fluoropyrrolidine

 [0595] [Chem 112]

[0596] Reference Example 3 1- (6-Methoxy-1-pyridyl) 5- (2 Pyridyl) 1H Pyrazolu 3-Hydronic acid (318 mg) and Reference Example 24 (3S) -3 Fluoropyrrolidine hydrochloride (126 mg) was used to give the title compound (69 mg, 19%) as a solid in the same manner as in Example 5.

 'H-NMR (400MHz, CDC1) δ: 2.01— 2.09 (1Η, m), 2.28— 2.35 (1Η,

 Three

 m), 3.76-4.20 (3Η, m), 3.96 (3Η, s), 4.44—4.49 (1H, m), 5.32 (1H

, dd, J = 52.6, 4.3Hz), 6.76 (1H, d, J = 8.8Hz), 7.22— 7.28 (2H, m),

7.46 (1H, dd, J = 7.9, 2.8Hz), 7.57—7.61 (1H, m), 7.72 (1H, td, J = 7

.7, 1.7Hz), 8.14 (1H, d, J = 2.7Hz), 8.51 (1H, t, J = 2.4Hz).

 ESI— MSm / z: 368 (M + H) +.

 Elemental analysis: C H FN O · 0.25H O

 19 18 5 2 2

 Theoretical values: C, 61.37; H, 5.01; N, 18.83.

 Found: C, 61.51; H, 4.74; N, 18.95.

 [0597] [Example 25] (2S, 5R) —1— [1— (6-Methoxy-3-pyridyl) -5- (2 pyridyl)

-1H-pyrazole 3 carbonyl] -2-methoxymethyl-5-methylpyrrolidine [0598] [Chem 113]

[0599] Reference Example 3 1- (6-Methoxy-1-pyridyl) 5- (2 Pyridyl) 1H Pyrazole-3-carboxylic acid (385 mg) and Reference Example 29 (2S, 5R) -2-methoxymethyl- The title compound (158 mg, 30%) was obtained as an oil in the same manner as in Example 5 using 5-methylpyrrolidine hydrochloride (215 mg).

 'H-NMR (400MHz, CDC1) δ: 1.12 and 1.31 (3Η, d, J = 6.3Hz), 1.5

 Three

 5-2.30 (3H, m), 3.24— 5.25 (6H, m), 3.38 and 3.40 (3H, s), 3.95 and 3.96 (3H, s), 6.73 and 6.77 (1H, s), 7.22— 7.24 (1H , m), 7.4

7-7.49 (1H, m), 7.57— 7.61 (1H, m), 7.70— 7.74 (1H, m), 8.09— 8

13 (1H, m), 8.49-8.51 (1H, m)

ESI-MSm / z: 408 (M + H) ⁺ .

[0600] [Example 26] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H-pyrazole-3-carbonyl] -2,5-dimethylpyrrolidine

[0601] [Chem 114]

参考例 4の 1— (6—メトキシ一 3 ピリダジ -ル） 5— (2 ピリジル） 1H ピラゾ ール一 3 カルボン酸（297mg)と 2, 5 ジメチルピロリジン（lOOmg)とを用いて、 実施例 5と同様の方法で標題ィ匕合物（227mg, 61%)を固体として得た。

Using Reference Example 4 1- (6-Methoxy-1-pyridazil) 5- (2 Pyridyl) 1H Pyrazole 1-3 Carbonic acid (297 mg) and 2,5 Dimethylpyrrolidine (lOOmg) Example 5 In the same manner, the title compound (227 mg, 61%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.10—1.52 (6Η, m), 1.57—1.74 (2Η,

 Three

m), 1.96-2.35 (2H, m), 4.11 (3H, s), 4.35— 5.16 (2H, m), 7.12— 7 .23 (3H, m), 7.59— 7.62 (1H, m), 7.73— 7.83 (2H, m), 8.40 (1H, d, J = 3.2 Hz).

 ESI— MSm / z: 379 (M + H) +.

 Elemental analysis: as C H N O

 20 22 6 2

 Theoretical values: C, 63.48; H, 5.86; N, 22.21.

 Found: C, 63.23; H, 5.85; N, 22.20.

[0603] [Example 27] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H-pyrazole-3 carbonyl] 2 methylpyrrolidine

[0604] [Chemical 115]

[0605] Using Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo 1-Lu 3-Strength Rubonic acid (297 mg) and 2 Methylpyrrolidine (106 μ 1) In the same manner as in Example 5, the title compound (153 mg, 42%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.24 (3Χ1 / 3Η, d, J = 6.3Hz), 1.35 (3

 Three

 Χ2 / 3Η, d, J = 6.3Hz), 1.61— 2.11 (4H, m), 3.70—4. 10 (2H, m), 4. 10 (3H, s), 4.44 (1X2 / 3H, dd, J = 10.5, 6.3Hz), 5.00 (1X1 / 3H, t, J = 6.3Hz), 7.11-7.15 (1H, m), 7.19— 7.23 (2H, m), 7.59— 7.62 (1H, m), 7.75 (1H, t, J = 7.7Hz), 7.81 (1H, d, J = 9.3Hz), 8.40 (1H, t, J = 3.7Hz).

 ESI— MSm / z: 365 (M + H) +.

 Elemental analysis: as C H N O

 19 20 6 2

 Theoretical values: C, 62.62; H, 5.53; N, 23.06.

 Found: C, 62.33; H, 5.52; N, 22.96.

[Example 28] 1— [1 (6-Methoxy-3 pyridyl) -5- (2 pyridyl) 1H villa Zoru

 [0607] [Chem 116]

[0608] Using Reference Example 3 1- (6-Methoxy-1-pyridyl) -5- (2 Pyridyl) 1H Pyrazolu 3-Strong Rubonic Acid (296 mg) and 2,5 Dimethylpyrrolidine (lOOmg) The title compound (105 mg, 28%) was obtained as a solid in the same manner as in Example 5.

 'H-NMR (400MHz, CDC1) δ: 1.10—1.45 (6Η, m), 1.60— 2.15 (4Η,

 Three

 m), 3.96 (3H, s), 4.33 (1H, s), 4.85 (1H, s), 6.74 (1H, d, J = 8.8Hz),

7.20-7.26 (2H, m), 7.47 (1H, d, J = 7.8Hz), 7.57 (1H, dd, J = 8.8, 2

.7Hz), 7.72 (1H, td, J = 7.8, 1.6Hz), 8.14 (1H, d, J = 2.7Hz), 8.50 (1

(H, d, J = 4.6Hz).

 ESI— MSm / z: 378 (M + H) +.

 Elemental analysis: as C H N O

 21 23 5 2

 Theoretical values: C, 66.83; H, 6. 14; N, 18.55.

 Found: C, 66.57; H, 6. 13; N, 18.55.

[Example 29] 1- [1 (6-Methoxy-3 pyridyl) -5- (2 pyridyl) 1H virazole 3 carbonyl] 2 methylpyrrolidine

[0610] [Chemical 117]

[0611] 1- (6-Methoxy-1-pyridyl) -5- (2 pyridyl) 1H pyrazol of Reference Example 3 The title compound (219 mg, 60%) was obtained as a solid in the same manner as in Example 5 using 1-3-carboxylic acid (296 mg) and 2-methylpyrrolidine (106 μ1).

 'H-NMR (400MHz, CDC1) δ: 1.23 (3Χ1 / 3Η, d, J = 6.3Hz), 1.34 (3

 Three

 Χ2 / 3Η, d, J = 6.3Hz), 1.61− 2.32 (3H, m), 3.70−4.53 (3H, m), 3.95 (3X2 / 3H, s), 3.96 (3X1 / 3H, s), 4.44 (1X2 / 3H, dd, J = 10.7, 6.3Hz), 5.04 (1X1 / 3H, br s), 6.74 (1H, d, J = 8.8Hz), 7.20— 7.23 (2 H, m), 7.47 (1H, t, J = 8.1 Hz), 7.56-7.61 (1H, m), 7.69-7.74 (1H, m), 8.14 (1H, q, J = 2.9Hz), 8.50 (1H, d, J = 4.9Hz).

 ESI MSm / z: 364 (M + H) +.

 Elemental analysis: as C H N O

 20 21 5 2

 Theoretical values: C, 66.10; H, 5.82; N, 19.27.

 Found: C, 66.09; H, 5.76; N, 19.34.

[0612] [Example 30] 1— [1- (6-Methoxy-1-pyridyl) 5- (4-pyrimidyl) -1-H-pyrazole 3-carbonyl] 4 Methylbiperazine

[0613] [Chemical 118]

参考例 16の 1— (6—メトキシ一 3 ピリジル） -5- (4 ピリミジ-ル）一 1H—ビラ ゾールー 3—力ルボン酸（50mg)と N—メチルビペラジン（28 μ 1)とを用いて、実施例 5と同様の方法で標題ィ匕合物（51mg, 76%)を固体として得た。

Using Reference Example 16 1- (6-Methoxy-1-pyridyl) -5- (4-Pyrimidyl) -1- 1H-virazol-3-strong rubonic acid (50 mg) and N-methylbiperazine (28 μ 1), In the same manner as in Example 5, the title compound (51 mg, 76%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.33 (3Η, s), 2.43—2.55 (4Η, m), 3.8

 Three

0-3.90 (2H, m), 3.99 (3H, s), 4.06—4.13 (2H, m), 6.82 (1H, d, J = 8.8Hz), 7.34 (1H, s), 7.39 (1H, dd , J = 5.1, 1.2Hz), 7.61 (1H, dd, J = 8.8, 2.7Hz), 8.15 (1H, d, J = 2.7Hz), 8.75 (1H, d, J = 5.1 Hz), 9.09 (1 H, d, J = l.2 Hz). ESI— MSm / z: 380 (M + H) +.

[0615] [Example 31] (2S) -1 [1 (6-Methoxy-3 pyridazyl) -5- (2 pyridyl)

 -1H Pyrazole 3-Carbon] — 2 Fluoromethylpyrrolidine

[0616] [Chemical 119]

 [0617] Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo One-Lou 3-Strength Rubonic Acid (297 mg) and Reference Example 27 (2S) -2 fluoro The title compound (245 mg, 64%) was obtained as a solid in the same manner as in Example 5 using methylpyrrolidine hydrochloride (140 mg).

 'H-NMR (400MHz, CDC1) δ: 1.92— 2.08 (4Η, m), 3.71—4.82 (5Η,

 Three

 m), 4.11 (3H, s), 7.12— 7.16 (1H, m), 7.20— 7.27 (2H, m), 7.59— 7

.63 (1H, m), 7.73—7.82 (2H, m), 8.39—8.42 (1H, m).

 ESI— MSm / z: 383 (M + H) +.

[0618] [Example 32] 1— [5 -— (5-Methyl-2-virazil) —1— (6-Methyl-3-pyridyl)

) 1H pyrazole-3 carbo]-4 fluoropiperidine

[0619] [Chemical 120]

参考例 8の 5—（5—メチルー 2—ビラジ-ル）ー1 （6—メチルー 3 ピリジル）ー1 H ピラゾールー 3—力ルボン酸（0.230g)と参考例 19の 4 フルォロピペリジン塩 酸塩 (0. 141g)とを用いて、実施例 1と同様の方法で標題ィ匕合物（0.225g, 76%) を固体として得た。 Ή-NMR (400MHz, CDC1 ) δ :1.93— 2.00 (4H, m), 2.58 (3H, s), 2.6

5- (5-Methyl-2-virazil) -1 (6-methyl-3-pyridyl) -1 H pyrazole-3-strong rubonic acid (0.230 g) in Reference Example 8 and 4-fluoropiperidine hydrochloride in Reference Example 19 The title compound (0.225 g, 76%) was obtained as a solid in the same manner as in Example 1 using the salt (0.141 g). NMR-NMR (400MHz, CDC1) δ: 1.93— 2.00 (4H, m), 2.58 (3H, s), 2.6

 Three

 2 (3H, s), 3.69-3.72 (1H, m), 3.97—4.10 (2H, m), 4.22—4.26 (1H, m), 4.87-5.01 (1H, m), 7.20— 7.24 (2H, m ), 7.63 (1H, dd, J = 8.3, 2.7Hz), 8.34 (1H, m), 8.42 (1H, d, J = 2.7Hz), 8.62 (1H, d, J = l.5 Hz).

EI-MSm / z: 380 (M ⁺ ).

[0621] [Example 33] 4- [1- (6-Methoxy-3-pyridyl) -5- (1H pyrazole-3-yl) 1H-pyrazole-3 carbo] morpholine

[0622] [Chemical 121]

 [0623] 1- (6-Methoxy-1-pyridyl) 5- (1H-pyrazole-1-3-yl) — 1H Pyrazole-3-carboxylic acid (0.370 g) and morpholine (0.203 ml) of Reference Example 13 The title compound (0.241 g, 51%) was obtained as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 3.72— 3.85 (6Η, m), 3.98 (3Η, s), 4.1

 Three

 5-4.18 (2H, m), 6.13 (1H, d, J = 2.2Hz), 6.80 (1H, dd, J = 8.8, 0.5H z), 7.28 (1H, s), 7.54 (1H, d, J = 2.4Hz), 7.63 (1H, dd, J = 8.8, 2.7Hz

), 8.23-8.24 (1H, m), 10.89 (1H, br s).

 ESI— MSm / z: 355 (M + H) +.

[0624] [Example 34] 1- [1 (6-Methoxy-3-pyridyl) -5- (2 pyridyl) 1H virazol-3-carbonyl] 3-methoxypiperidine

[0625] [Chemical 122]

[0626] Using Reference Example 3 1- (6-Methoxy-1-pyridyl) 5- (2 Pyridyl) 1H Pyrazolu 3 Carboxylic Acid (250 mg) and Reference Example 28 3 Methoxypiperidine Hydrochloride (166 mg) The title compound (285 mg, 86%) was obtained as a solid in the same manner as in Example 1.

H—NMR (400MHz, CDC1) δ: 1.59— 1.63 (2Η, m), 1.85 (1H, m), 2.

 Three

 03 (1H, m), 3.31 (3 / 2H, s), 3.35—3.51 (3H, m), 3.45 (3 / 2H, s), 3. 95-3.95 (3H, m), 4.19—4.45 (2H , m), 6.75 (1H, d, J = 8.8Hz), 7.10 -7. 14 (1H, m), 7.22— 7.25 (1H, m), 7.40— 7.45 (1H, m), 7.59 (1H, dd , J = 8.8, 2.7Hz), 7.73— 7.69 (1H, m), 8.11 (1H, s), 8.51 (1H, s). EI— MSmZz: 393 (M +).

 Elemental analysis: as C H N O

 21 21 5 3

 Theoretical values: C, 64.11; H, 5.89; N, 17.80.

 Found: C, 63.89; H, 5.87; N, 17.63.

[0627] [Example 35] 4— [1— (6-Methoxy-3-pyridyl) -5- (1H—pyrrole 3-yl)

 -1H pyrazole-3-carbol] morpholine

[0628] [Chemical 123]

参考例 30の 1— (6—メトキシ— 3 ピリジル）—5— (1H ピロール— 3—ィル） - H ピラゾール 3 カルボン酸（ 200mg)とモルホリン（ 184 1)とを用いて、実施 例 1と同様の方法で標題化合物（230mg, 84%)を泡状物質として得た。

Using Reference Example 30 1- (6-methoxy-3-pyridyl) -5- (1H pyrrole-3-yl) -H pyrazole 3 carboxylic acid (200 mg) and morpholine (184 1) The title compound (230 mg, 84%) was obtained as a foam in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 3.68— 3.83 (6Η, m), 3.98 (3Η, s), 4.1

 Three

 6 (2H, br s), 6.03— 6.6 (1H, m), 6.62— 6.65 (1H, m), 6.71— 6.75 (1

H, m), 6.79 (1H, d, J = 8.8Hz), 6.84 (1H, s), 7.61 (IH, dd, J = 8.8, 2.

7Hz), 8.24 (IH, d, J = 2.7Hz), 8.41 (IH, br s).

 FAB MSm / z: 354 (M + H) +.

[0630] [Example 36] 1— [1— (6-Methoxy-3-pyridyl) -5- (1-methyl-1H-pyrazolu 3-yl) 1H-pyrazole-3-carbol] -4-methyl 3— Oxopipera Gin

[0631] [Chemical 124]

[0632] 1- (6-Methoxy-3-pyridyl) of Reference Example 31 5- (1-Methyl 1H pyrazole-3-yl) 1H Pyrazole-3-carboxylic acid (0.119 g) and 1-methyl pipette of Reference Example 46 The title compound (0.094 g, 59%) was obtained as an amorphous substance in the same manner as in Example 5 using lazine-2-one (0.139 g).

 'H-NMR (400MHz, CDC1) δ: 3.01 (3Η, s), 3.42—3.50 (2Η, m), 3.8

 Three

 7 (3H, s), 3.98 (3H, s), 3.95—4.10 (1H + 1HX 1/2, m), 4.36—4.47 (1H + 1HX1 / 2, m), 4.80 (1H, br), 5.95— 6.06 (IH, m), 6.78 (1HX1 / 2, s), 6.80 (lHXl / 2, s), 7.09 (1H, br), 7.30 (1H, br), 7.59—7.65 (IH, m), 8.21 ( IH, br).

 ESI— MSm / z: 396 (M + H) +.

 [0633] [Example 37] 4- [1 (6-Methoxy-3 pyridyl) -5- (1-methyl-1H-pyrazolol 3 yl) -1H-pyrazole 3 carbol] morpholine

[0634] [Chemical 125]

[0635] 1- (6-Methoxy-1-pyridyl) 5- (1-methyl 1H pyrazole-3-yl) 1H pyrazole-3-carboxylic acid (0.225 g) and morpholine (0.164 ml) in Reference Example 31 Was used to give the title compound (0.225 g, 81%) as a solid in the same manner as in Example 5.

 'H-NMR (400MHz, CDCl) δ: 3.66— 3.87 (6Η, m), 3.87 (3Η, s), 3.9

 Three

 7 (3H, s), 4.06-4.15 (2H, m), 5.99 (1H, d, J = 2.4Hz), 6.78 (1H, d, J = 8.8Hz), 7.04 (1H, s), 7.29 (1H , d, J = 2.4Hz), 7.63 (H, dd, J = 8.8, 3.0Hz), 8.21 (1H, d, J = 3.0Hz).

 ESI— MSm / z: 369 (M + H) +.

[0636] [Example 38] 1— [1— (6-Methyl-3 pyridyl) -5- (1-methyl-1H pyrrole

 3Hil) 1H Pyrazole-3Carbon] -4-Methyl-3-oxopiperazine

 [0637] [Chemical 126]

参考例 14の 1 （6—メチルー 3 ピリジル）ー5—（1ーメチルー 1H—ピロ一ルー 3 ィル） 1H ピラゾールー 3—力ルボン酸（0.251g)と参考例 46の 1ーメチルビ ペラジン一 2—オン (0.329g)とを用いて、実施例 5と同様の方法で、標題ィ匕合物（0 .225g, 67%)をアモルファス状物質として得た。

1 of Reference Example 14 (6-Methyl-3-pyridyl) -5- (1-Methyl-1H-Pyrroyl 3-yl) 1H Pyrazole 3-Strong Rubonic Acid (0.251g) and 1-Methylbiperazine 2-None of Reference Example 46 (0.329 g) was used to obtain the title compound (0.225 g, 67%) as an amorphous substance in the same manner as in Example 5.

'H-NMR (400MHz, CDCl) δ: 2.60 (3Η, s), 2.98 (3Η, s), 3.38—3.48 (2H + 1HX1 / 2, m), 3.58 (3H, s), 4.00 (1H, br), 4.39 (1Η + 1ΗΧ1 / 2, br), 4.78 (IH, br), 5.86 (IH, br), 6.44 — 6.52 (2H, m), 6.78 (1HX1 / 2, s), 6.83 (lHXl / 2, s), 7.16— 7.25 (1H, m), 7.55— 7.70 (1H, m), 8.52 (lHXl / 2, br), 8.57 (lHXl / 2, br).

 ESI— MSm / z: 379 (M + H) +.

 [0639] [Example 39] (2S) -1- [1- (6-Methoxy-3-pyridyl) -5- (1H-pyrrole-3 yl) 1H pyrazole-3 carbol] 2-Strength rubamoylpyrrolidine

[0640] [Chemical 127]

[0641] Reference Example 30 1- (6-Methoxy-1-pyridyl) 5-- (1H pyrrole 3-yl) 1 H Pyrazonole 3 Power Norebonic acid (0.250 g) and L prolinamide (0.120 g) In the same manner as in Example 1, the title compound (0.109 g, 32%) was obtained as a solid. 'H-NMR (400MHz, DMSO-d) δ: 1.77— 2.09 (4Η, m), 3.58 (IH, m)

 6

 , 3.90 (3H, s), 3.96 (1H, m), 4.40 (0.5H, dd, J = 8.42, 3.85Hz), 5.1 2 (0.5H, J = 8.54, 2.87Hz), 5.87 (1H, d, J = 2.87Hz), 6.72 (1H, m), 6.81 (IH, s), 6.93 (IH, dd, J = 20.4, 8.73Hz), 7.33 (IH, s), 7.75 (IH, ddd, J = 21.9, 8.73, 2.7Hz), 8.24 (IH, m), 11.05 (1H, br).

 FAB MSm / z: 381 (M + H) +.

 [0642] [Example 40] 4- [1- (6-Methoxy-3-pyridyl) -5- (1-methyl-1H-pyrrole 3 yl) -1H-pyrazole 3 carbol] morpholine

[0643] [Chemical 128]

[0644] Reference Example 32 1- (6-Methoxy-3 pyridyl) -5- (1-methyl 1H pyrrole-3 yl)-1H pyrazole mono-3-carboxylic acid (0.250 g) and morpholine (110 μ 1) In the same manner as in Example 1, the title compound (0.162 g, 53%) was obtained as a solid. 'H-NMR (400MHz, CDCl) δ: 3.60 (3Η, s), 3.72—3.79 (6Η, br), 3.9

 Three

 9 (3H, s), 4.15 (2H, br), 5.90 (1H, dd, J = 2.69, 1.83Hz), 6.47 (1H, t, J = l.83Hz), 6.51 (1H, t, J = 2.56Hz), 6.78 (1H, d, J = 8.79Hz), 6.7 9 (1H, s), 7.61 (1H, dd, J = 8.79, 2.69Hz), 8.24 (1H, d, J = 2.69Hz) FAB MSm / z: 368 (M + H) +.

 [Example 41] 1 [1- (6-Methoxy-3-pyridazil) 5- (1H-pyrrole 3-yl) 1H pyrazole-3 carbo] morpholine

 [0646] [Chemical 129]

参考例 33の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (1H ピロール— 3—ィル )— 1H ピラゾール 3 カルボン酸（0.250g)とモルホリン（ 115 1)とを用 、て、 実施例 1と同様の方法で、標題化合物（0. 135g, 42%)を固体として得た。

Using Reference Example 33 1- (6-methoxy-3pyridazil) -5- (1H pyrrole-3-yl) -1H pyrazole 3 carboxylic acid (0.250 g) and morpholine (115 1), In the same manner as in Example 1, the title compound (0.135 g, 42%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 3.71 (2Η, br), 3.80 (4Η, br), 4.10 (2H

 Three

, br), 4.19 (3H, s), 6.19 (1H, dd, J = 4.15, 2.44Hz), 6.75 (1H, dd, J = 4.88, 2.19Hz), 6.85 (1H, s), 7.03 ( 1H, m), 7.08 (1H, d, J = 9.28Hz), 7.55 (1H, d, J = 9.28Hz). FAB— MSm / z: 355 (M + H).

[0648] [Example 42] 1— [1 (6-Methyl-3 pyridazil) 5— (1-Methyl-1H pyro 1ru 3 yl) 1H Pyrazole-3 carbol] —4, 4-difluoro Verizin

 [0649] [Chemical 130]

[0650] Reference Example 36 1- (6-Methyl-3 pyridazil) -5- (1-Methyl 1H pyrrole 3-yl) 1H Pyrazole mono 3-carboxylic acid (0.245 g) and Reference Example 18 The title compound (0.295 g, 88%) was obtained as a solid in the same manner as in Example 1 by using 4,4 difluoropiperidine hydrochloride (0.217 g).

 'H-NMR (400MHz, CDC1) δ: 1.97— 2.15 (4Η, m), 2.79 (3Η, s), 3.6

 Three

 3 (3H, s), 3.91 (2H, br), 4.13 (2H, br), 6.11— 6.15 (1H, m), 6.51— 6

.57 (1H, m), 6.81 (1H, s), 6.92— 6.97 (1H, m), 7.46 (1H, d, J = 8.8H z), 7.61 (1H, d, J = 8.8Hz).

ESI-MSm / z: 387 (M + H) ⁺ .

[0651] [Example 43] 1— [5— (1H-imidazole-2-yl) -1-1- (6-methoxy-3-pyridyl) 1H-pyrazole-3-carbol] -4-methoxypiperidine

[0652] [Chemical 131]

参考例 43の 5— (1H—イミダゾールー 2—ィル）—1— (6—メトキシ— 3 ピリジル) 1H ピラゾールー 3—力ルボン酸ェチルエステル（0.210g)のエタノール（5ml) とテトラヒドロフラン（2.5ml)の混合懸濁液に 1N水酸ィ匕ナトリウム水溶液（1.00ml) を加え、室温で 5時間攪拌した。さらに反応液に 1N水酸化ナトリウム水溶液（1.00m 1)を加え 20.5時間攪拌した。反応液に 1N塩酸水溶液（2.00ml)を加え、反応溶媒 を減圧下留去し 5— (1H—イミダゾールー 2—ィル） 1— (6—メトキシ一 3 ピリジ ル） 1H—ピラゾールー 3—力ルボン酸を得た。このカルボン酸と参考例 23の 4ーメ トキシピペリジン塩酸塩 (0.218g)とを用いて、実施例 1と同様の方法で、標題化合 物（73.7mg, 28%)を固体として得た。

Reference Example 43 5— (1H-imidazole-2-yl) —1— (6-methoxy-3-pyridyl) To a mixed suspension of 1H pyrazole-3-ethyl rubonic acid ethyl ester (0.210 g) in ethanol (5 ml) and tetrahydrofuran (2.5 ml) was added 1N sodium hydroxide aqueous solution (1.00 ml), and the mixture was stirred at room temperature for 5 hours. Further, 1N aqueous sodium hydroxide solution (1.00 ml) was added to the reaction solution, and the mixture was stirred for 20.5 hours. To the reaction solution was added 1N aqueous hydrochloric acid (2.00 ml), and the reaction solvent was distilled off under reduced pressure. 5- (1H-imidazole-2-yl) 1- (6-methoxy-1-pyridyl) 1H-pyrazole-3-strong rubon The acid was obtained. Using this carboxylic acid and 4-methoxypiperidine hydrochloride (0.218 g) of Reference Example 23, the title compound (73.7 mg, 28%) was obtained as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 1.64—1.77 (2Η, m), 1.87—1.99 (2Η,

 Three

 m), 3.38 (3H, s), 3.49— 3.62 (2H, m), 3.78— 3.86 (1H, m), 3.93—4.03 (1H, m), 3.97 (3H, s), 4.21—4.28 ( 1H, m), 6.77 (1H, dd, J = 8.8, 0.5Hz), 7.10 (2H, br s), 7.16 (1H, s), 7.64 (1H, dd, J = 8.8, 2.7Hz), 8.26 ( 1H, dd, J = 2.7, 0.5Hz), 11.05 (1H, br s).

 ESI— MSm / z: 383 (M + H) +.

 [Example 44] 1 [5- (5 cyano 2 pyridyl) -1-1 (6-methyl-3 pyridyl) 1H pyrazole-3 carbonyl] —4,4-difluoropiperidine

 [0655] [Chemical 132]

参考例 37の 5— (5 シァノ 2 ピリジル） 1— (6—メチル 3 ピリジル） 1H —ピラゾールー 3—カルボン酸（0.740g)と参考例 18の 4, 4 ジフルォロピペリジン 塩酸塩 (0.458g)とを用いて、実施例 1と同様の方法で、標題化合物（0.827g, 84 %)を固体として得た。

Reference Example 37 5 -— (5 Cyan-2-pyridyl) 1- (6-Methyl 3-pyridyl) 1H —Pyrazole-3-carboxylic acid (0.740 g) and Reference Example 18, 4, 4 difluoropiperidine hydrochloride (0.458 g) In the same manner as in Example 1, the title compound (0.827 g, 84%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.08— 2.10 (4Η, m), 2.64 (3Η, s), 3.9

 Three

3 (2H, m), 4.20 (2H, m), 7.25— 7.27 (1H, m), 7.32 (1H, s), 7.59— 7. 62 (2H, m), 8.00 (1H, dd, J = 8.2, 2.1 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.

70-8.71 (1H, m).

EI-MSm / z: 408 (M ⁺ ).

 [Example 45] 1— [5 -— (5--Rubamoyl-2-pyridyl) -1- (6-methyl-3-pyridyl) 1H-pyrazole 3-carbonyl] 4, 4 Difluoropiperidine

 [0657] [Chemical 133]

[0658] Example 44 1- [5- (5 Cyan-2-pyridyl) 1- (6-Methyl-3-pyridyl) — 1H pyrazole- 3-carbol] — 4, 4 Difluoropiperidine (0.410 g) To a mixed solution of ethanol (8.2 ml) and tetrahydrofuran (8.2 ml) was added 1N aqueous sodium hydroxide solution (5.02 ml) at room temperature, and the mixture was heated to reflux for 15 minutes. After cooling with air, the reaction mixture was partitioned by adding a mixed solvent of water and chloroform-methanol (10: 1 (vZv)), and the solvent in the organic layer was distilled off under reduced pressure. The title compound (0.237 g, 55%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.07 (4Η, m), 3.32 (3Η, s), 3.79 (

 6

 2H, m), 4.06 (2H, m), 7.34— 7.36 (2H, m), 7.63 (1H, br s), 7.69— 7

.71 (1H, m), 7.83-7.85 (1H, m), 8.15 (1H, br s), 8.27— 8.30 (1H, m), 8.43 (1H, d, J = 2.4Hz), 8.85— 8.86 ( 1H, m).

EI-MSm / z: 426 (M ⁺ ).

[0659] [Example 46] 1- [1 (6-Methoxy-3-pyridyl) -5- (2 pyrajur) 1H-Pyrazole-3-carbonyl] -4,4-difluoropiperidine

[0660] [Chemical 134]

[0661] Reference Example 6 1- (6-Methoxy-1-pyridyl) -5- (2 Pyrazyl) 1H Pyrazo One-Lou 3-Strong Rubonic Acid (0.231 g) and Reference Example 18, 4, 4-difluo The title compound (242 mg, 77%) was obtained as a solid in the same manner as in Example 1 using lopiperidine hydrochloride (0.222 g).

 'H-NMR (400MHz, CDC1) δ: 2.05— 2.14 (4Η, m), 3.91— 3.95 (2Η,

 Three

 m), 3.97 (3H, s), 4.19-4.22 (2H, m), 6.80 (1H, dd, J = 8.8, 0.5Hz), 7.29 (1H, s), 7.59 (1H, dd, J = 8.8, 2.7Hz), 8.13 (1H, dd, J = 2.7, 0.7Hz), 8.48 (1H, dd, J = 2.4, 1.5Hz), 8.52 (1H, d, J = 2.4Hz), 8.73 (1 H, d, J = l.5Hz).

ESI-MSm / z: 401 (M + H) ⁺ .

 Elemental analysis: as C H FN O

 19 18 2 6 2

 Theoretical values: C, 57.00; H, 4.53; N, 20.99; F, 9.49.

 Found: C, 56.78; H, 4.40; N, 20.92; F, 9.36.

[0662] [Example 47] 1- [1 (6-Methoxy-3 pyridyl) -5- (2 pyrajur) 1H pyrazole- ₃ carbonyl] ₄ -methoxypiperidine

[0663] [Chemical 135]

参考例 6の 1— (6—メトキシ一 3 ピリジル） -5- (2 ピラジュル）一 1H ピラゾ 一ルー 3—力ルボン酸（0.231g)と参考例 23の 4ーメトキシピペリジン塩酸塩（0.21 8g)とを用いて、実施例 1と同様の方法で標題ィ匕合物（243mg, 78%)を固体として 得た。

Reference Example 6 1- (6-Methoxy-1-pyridyl) -5- (2 Pyraduryl) -1-H Pyrazo One-Loo 3-Strong Rubonic Acid (0.231 g) and 4-Methoxypiperidine Hydrochloride of Reference Example 23 (0.21) In the same manner as in Example 1, the title compound (243 mg, 78%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.63— 1.75 (2Η, m), 1.89— 2.00 (2Η,

 Three

 m), 3.38 (3H, s), 3.48—3.59 (2H, m), 3.72—3.79 (1H, m), 3.97 (3H, s), 4.06-4.12 (1H, m), 4.25—4.31 (1H, m), 6.79 (1H, dd, J = 8.8, 0.5Hz), 7.23 (1H, s), 7.61 (1H, dd, J = 8.8, 2.7Hz), 8.12 (1H, dd, J = 2.7, 0.5Hz), 8.48 (1H, dd, J = 2.4, 1.5Hz), 8.51 (1H, d, J = 2.4Hz), 8.73 (1H, d, J = l.5Hz).

 ESI— MSm / z: 395 (M + H) +.

 Elemental analysis: as C H N O

 20 22 6 3

 Theoretical values: C, 60.90; H, 5.62; N, 21.31.

 Found: C, 60.69; H, 5.60; N, 21.12.

[0665] [Example 48] 1- [1 (6-Methoxy-3 pyridyl) -5- (1-methyl-1H-imidazo one-ru four-yl) 1H pyrazole-three carbole]-4,4-difluoropiveri gin

 [0666] [Chemical 136]

[0667] Reference Example 34 1- (6-Methoxy-1-pyridyl) 5- (1-Methyl 1H-imidazole 4-yl) —1H Pyrazole-3-carboxylic acid (183 mg) and Reference Example 18 4, 4 — The title compound (182 mg, 74%) was obtained as a solid in the same manner as in Example 5 using difluoropiperidine hydrochloride (116 mg).

 'H-NMR (400MHz, CDC1) δ: 2.04 (4Η, br s), 3.66 (3H, s), 3.90 (2H

 Three

, s), 3.98 (3H, s), 4.15 (2H, s), 6.69 (1H, s), 6.80 (1H, d, J = 8.8Hz), 7.00 (1H, s), 7.41 (1H, s) , 7.68 (1H, dd, J = 8.8, 2.7Hz), 8.24 (1H, d , J = 2.7Hz).

 ESI MSm / z: 403 (M + H) +.

[0668] [Example 49] 4 [5- (3 Hydroxymethyl-1H-pyrrole-1-yl) -1-1- (6-Methoxy-3-pyridyl) -1H-pyrazole 3-carbol] morpholine

[0669] [Chemical 137]

[0670] Methanol of 5- (3 formyl 1H pyrrole 1 yl) 1 6 -methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (0.6 07 g) under cooling at 0 ° C in Reference Example 38 (20 ml) and dichloromethane (10 ml) mixed solution, sodium borohydride (36.7 mg) was added and stirred for 35 minutes and then at room temperature for 21 hours. The reaction mixture was mixed with dichloromethane and saturated aqueous ammonium chloride solution, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to give 5- (3 hydroxymethyl-1H-pyrrole-1-yl) -1- (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester . This ethyl ester was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (5.5 ml) was added, and the mixture was stirred at room temperature for 20.5 hours. Jetyl ether and 1N aqueous hydrochloric acid solution were separated into the reaction solution, and the aqueous layer was saturated with sodium chloride, followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure. 5- (3 Hydroxymethyl-1H pyrrole-1-yl) -1- (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid (0.595 g, quantitative) Was obtained as an amorphous substance. Using the carboxylic acid (0.298 g) and morpholine (0.140 ml), the title compound (217 mg, 63%) was obtained as an amorphous substance in the same manner as in Example 1.

'H-NMR (400MHz, CDC1) δ: 3.74— 3.83 (6Η, m), 3.95 (3Η, s), 4.1 6—4.19 (2H, m), 4.55 (2H, s), 6.33 (1H, dd, J = 2.9, 1.7Hz), 6.62 (1 H, dd, J = 2.7, 2.4Hz), 6.66— 6.67 (1H , m), 6.73 (1H, d, J = 8.8Hz), 6.84 (1H, s), 7.32 (1H, dd, J = 9.0, 2.7Hz), 8.01 (1H, d, J = 2.7Hz) .ESI MSm / z: 384 (M + H) +.

 [0671] [Example 50] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H-pyrazole-3-carbonyl] -3,3-difluoropyrrolidine

 [0672] [Chemical 138]

[0673] Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo One-Lou 3-Strength Rubonic Acid (297 mg) and Reference Example 44 3, 3 Difluoropyrrolidine Hydrochloride The title compound (31 lmg, 80%) was obtained as a solid in the same manner as in Example 5 using the salt (144 mg).

 'H-NMR (400MHz, CDC1) δ: 2.35—2.52 (2Η, m), 3.95 (1Η, t, J = 7.

 Three

 6Hz), 4.04 (1H, t, J = 13.1Hz), 4.12 (3H, s), 4.33 (1H, t, J = 7.4Hz), 4.42 (1H, t, J = 12.9Hz), 7.15 (1H, t, J = 9.8Hz), 7.22 (1H, dd, J = 7.6, 4.9Hz), 7.27 (1H, s), 7.62 (1H, d, J = 7.8Hz), 7.73— 7.79 (2H, m), 8.40 (1H, d, J = 4.9Hz).

ESI-MSm / z: 387 (M + H) ⁺ .

 [0674] [Example 51] 1— [1— (6-Methoxy-3-pyridazil) -5- (5-methyl-2-pyridyl) 1H-pyrazole-3-carbol] —4-methoxypiperidine

[0675] [Chemical 139]

[0676] Reference Example 39 1- (6-Methoxy-3 pyridazil) -5- (5-Methyl-2-pyridyl) — 1H Pyrazole-3-carboxylic acid (500 mg) and 4-methoxypiperidine hydrochloride of Reference Example 23 The title compound (236 mg, 36%) was obtained as a solid in the same manner as in Example 5 using the salt (372 mg).

 'H-NMR (400MHz, CDCl) δ: 1.60 (2Η, br), 1.96 (2Η, br), 2.33 (3H

 Three

 , s), 3.38 (3H, s), 3.51 (2H, br), 3.71 (1H, br), 4.09 (4H, br), 4.24 (1 H, br), 7.02 (1H, s), 7.12 (1H , d, J = 9.16Hz), 7.45 (1H, d, J = 7.94Hz), 7.54 (1H, m), 7.81 (1H, d, J = 9.16Hz), 8.25 (1H, s).

 FAB MSm / z: 409 (M + H) +.

 [0677] [Example 52] 4- [1 (6-Methoxy-3 pyridazil) -5- (5-methyl-2-pyridyl) 1H-pyrazole-3 carbol] morpholine

 [0678] [Chemical 140]

参考例 39の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (5—メチル—2 ピリジル） — 1H ピラゾール 3 カルボン酸（ 500mg)とモルホリン（ 210 1)とを用いて、実 施例 5と同様の方法で標題化合物（279mg, 45%)を固体として得た。

Example 39 using 1- (6-methoxy-3pyridazil) -5- (5-methyl-2pyridyl) — 1H pyrazole 3 carboxylic acid (500 mg) and morpholine (210 1) in Reference Example 39 The title compound (279 mg, 45%) was obtained as a solid in the same manner as in 5.

 'H-NMR (400MHz, CDCl) δ: 2.33 (3Η, s), 3.72 (2Η, br), 3.81— 3.8

 Three

3 (4H, br), 4.12 (5H, br), 7.10 (1H, s), 7.12 (1H, d, J = 9.16Hz), 7.47 (1H, d, J = 7.94Hz), 7.54 ( 1H, dd, J = 7.94, 1.83Hz), 7.75 (1H, d, J = 9.16Hz), 8.23 (IH, d, J = l.83Hz).

 FAB MSm / z: 381 (M + H) +.

[0680] [Example 53] 1— [1 (6-Methoxy-3 pyridazil) -5- (5-methyl-2-pyridyl) 1 H pyrazole 3 carbonyl] 4 Methylpiperazine

[0681] [Chemical 141]

[0682] Reference Example 39 1— (6-Methoxy-3 pyridazil) —5— (5-Methyl-2-pyridyl)

 The title compound (220 mg, 34%) was obtained as a solid in the same manner as in Example 5 using 1H pyrazole-3-carboxylic acid (500 mg) and N-methylbiperazine (270 μ1). 'H-NMR (400MHz, CDCl) δ: 2.33 (6Η, s), 2.44 (2Η, br), 2.51 (2H,

 Three

 br), 3. 85 (2H, br), 4. 07 (2H, br), 4. 12 (3H, s), 7. 06 (IH, s), 7. 12 (IH

, d, J = 9. 28Hz), 7. 46 (1H, d, J = 7. 94Hz), 7. 54 (1H, d, J = 7. 94Hz), 7

79 (1H, d, J = 9. 28Hz), 8. 24 (IH, s).

 FAB MSm / z: 394 (M + H) +.

[0683] [Example 54] 1— [1 (6-methyl-3-pyridyl) 5- (4-methyl-2-pyridyl)

 1H pyrazole-3 carbonyl] -4-methoxypiperidine

[0684] [Chemical 142]

[0685] Reference Example 40 1- (6-Methyl-3 pyridyl) -5- (4-Methyl-2 pyridyl) 1 H The title compound (219 mg, 54%) was prepared in the same manner as in Example 5 using pyrazole-3-strong rubonic acid (300 mg) and 4-methoxypiperidine hydrochloride (227 mg) of Reference Example 23. Obtained as Morphus.

 'H-NMR (400MHz, CDCl) δ: 1.69 (2Η, brs), 1.94 (2Η, brs), 2.36 (3

 Three

 H, s), 2.58 (3H, s), 3.38 (3H, s), 3.50 (2H, m), 3.74 (1H, m), 4.09 (1 H, brs), 4.26 (1H, br s), 7.05 (1H, s), 7.07 (1H, s), 7.17 (1H, d, J = 8.18Hz), 7.30 (1H, s), 7.62 (1H, dd, J = 8. 18, 2.56Hz), 8.34 (1H, d, J = 5.01Hz), 8.39 (1H, d, H = 2.56Hz).

 FAB— MSm / z: 392 (M + H) +.

 [Example 55] 4- [1 (6-Methoxy-3 pyridyl) -5- (5-methyl-2-pyrazole) 1H-pyrazole-3 carbo] morpholine

 [0687] [Chemical 143]

[0688] 1- (6-Methoxy-3-pyridyl) -5- (5-methyl-2pyrazyl) in Reference Example 41 — 1H Pyrazole mono-3-carboxylic acid (0.250 g) and morpholine (0.105 ml) Was used to obtain the title compound (0.174 g, 56%) as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDCl) δ: 2.58 (3Η, s), 3.74—3.83 (6Η, m), 3.9

 Three

 7 (3H, s), 4. 15-4.17 (2H, m), 6.79 (1H, d, J = 8.8Hz), 7.24 (1H, s),

7.59-7.62 (1H, m), 8. 12 (1H, d, J = 2.4Hz), 8.36 (1H, d, J = l.5Hz)

, 8.59 (1H, d, J = l.5Hz).

EI-MSm / z: 380 (M ⁺ ).

 Elemental analysis: C H N O · 0.25H O

 19 20 6 3 2

 Theoretical values: C, 59.29; H, 5.37; N, 21.83.

Found: C, 59.33; H, 5.21; N, 21.73. [0689] [Example 56] 1— [5 -— (5-amino-2-virazil) 1 (6-methoxy-3-pyridyl)

) —1H Pyrazole—3-Carbon] — 4, 4 Difluoropiperidine

[0690] [Chemical 144]

[0691] 1) 1 [5— (5-tert-Butoxycarbolamino 2 pyridyl) 1 (6-methoxy-3-pyridyl) 1H pyrazole 3 carbonyl] 4, 4 Difluoropiberidine

 Reference Example 42 5- (5-tert-butoxycarbo-lumino 2-pyrazuryl) -1 (6-methoxy-1-pyridyl) 1H pyrazole-3-carboxylic acid (0.290 g) and Reference Example 18, 4, 4 difluoropiperidine hydrochloride 1 [5- (5-tert-butoxycarbo-lumino 2-pyrazur) 1 1 (6-methoxy-3-pyridyl) 1H pyrazole 3 carbonyl] 4 using salt (0.133 g) in the same manner as in Example 1. , 4 Difluoropiveridine (0.306 g, 84%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.54 (9Η, s), 2.08 (4Η, m), 3.92 (2H,

 Three

 m), 3.97 (3H, s), 4.20 (2H, m), 6.78 (1H, dd, J = 8.8, 0.7Hz), 7. 17 (1H, s), 7.40 (1H, s), 7.60 (1H , dd, J = 8.8, 2.9Hz), 8.11— 8.12 (1H, m), 8.33 (1H, d, J = l.5Hz), 9.17 (1H, d, J = l.5Hz).

EI-MSm / z: 515 (M ⁺ ).

[0692] 2) Title compound

1 [5-(5-tert-butoxycarbolamino 2 pyridyl) 1 1 (6-methoxy-3 pyridyl) -1H pyrazole 3-carbol] — 4, 4 Difluoropiperidine (0.300 g) in dichloromethane (6 ml ) To the solution was added trifluoroacetic acid (3 ml) at room temperature and stirred for 105 minutes. A saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction solution, and the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent under reduced pressure was obtained. The residue was purified by silica gel column chromatography (methanol / chloroform form) to obtain the title compound (0.189 g, 77%) as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.08 (4Η, m), 3.92 (2Η, m), 3.96 (3H,

 Three

 s), 4.19 (2H, m), 4.78 (2H, br s), 6.78 (1H, d, J = 8.8Hz), 7.06 (1H, s), 7.59 (1H, dd, J = 8.8, 2.7Hz) , 7.87 (1H, d, J = l.5Hz), 8.10 (1H, d

, J = l.5Hz), 8.14 (1H, d, J = 2.7Hz).

 EI-MSm / z: 415 (M +).

 Elemental analysis: C H F N O · 0.25H O

 19 19 2 7 2 2

 Theoretical values: C, 54.35; H, 4.68; N, 23.35; F, 9.05.

 Found: C, 54.61; H, 4.50; N, 23.24; F, 9.31.

[0693] [Example 57] 4— [5— (5 amino-2-pyrazuryl) -1- (6-methoxy-1-pyridyl)

)-1H pyrazole-3-carbol] morpholine

[0694] [Chemical 145]

1) 4— [5— (5— tert-Butoxycarbo-lamino-2 pyridyl) — 1— (6-Methoxy-3-pyridyl) 1H pyrazole 3 carbo] morpholine

 Using Reference Example 42, 5- (5-tert-butoxycarbo-lumino 2-pyrazur) -1 (6-methoxy-1-pyridyl) 1H pyrazole-1-3-carboxylic acid (0.290 g) and morpholine (0.0919 ml) In the same manner as in Example 1, 4 [5— (5-tert-butoxycarbolamino-2-bilazil) 1- (6-methoxy-1-pyridyl) 1H pyrazole 3-carbol] morpholine (0.282 g, 83%) Was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.54 (9Η, s), 3.74—3.83 (6Η, m), 3.9

 Three

7 (3H, s), 4.16 (2H, m), 6.78 (1H, dd, J = 8.8, 0.7Hz), 7.17 (1H, s), 7.44 (1H, s), 7.60 (1H, dd, J = 8.8, 2.7Hz), 8.11— 8.12 (1H, m), 8.33 (1H, d, J = l.5Hz), 9.17 (1H, d, J = l.5Hz).

 EI-MSm / z: 481 (M +).

[0696] 2) Title compound

 Example 4 of [56- (5-tert-butoxycarbolamino 2 pyridyl) 1 1 1 (6-methoxy-3 pyridyl) -1H pyrazole-3-carbol] morpholine (0.276 g) ) To give the title compound (0.186 g, 84%) as a solid. 'H-NMR (400MHz, CDC1) δ: 3.73— 3.82 (6Η, m), 3.96 (3Η, s), 4.1

 Three

 4 (2H, m), 4.79 (2H, br s), 6.76— 6.78 (1H, m), 7.07 (1H, s), 7.59 (1

H, dd, J = 8.8, 2.7Hz), 7.87 (1H, d, J = l.5Hz), 8.10 (1H, d, J = l.5Hz)

), 8.13-8.14 (1H, m).

EI-MSm / z: 381 (M ⁺ ).

 Elemental analysis: C H N O · 0.25H O

 18 19 7 3 2

 Theoretical values: C, 56.02; H, 5.09; N, 25.41.

 Found: C, 56.14; H, 4.95; N, 25.12.

[0697] [Example 58] 1— [1— (6-Methoxy-3-pyridazil) -5- (1H-pyrrole-3-yl) 1H pyrazole-3 carbol] —4,4-difluo Lopiperidine

[0698] [Chemical 146]

参考例 33の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (1H ピロール— 3—ィル )—1H ピラゾールー 3—力ルボン酸（200mg)と参考例 18の 4, 4ージフルォロピ ペリジン塩酸塩（133mg)とを用いて、実施例 1と同様の方法で、標題ィ匕合物（117m g, 43%)を固体として得た。

Reference Example 33 1- (6-Methoxy-3 pyridazil) -5- (1H pyrrole-3-yl) -1H pyrazole-3-strong rubonic acid (200 mg) and 4,4-difluoropiperidine hydrochloride of Reference Example 18 The title compound (117 mg, 43%) was obtained as a solid in the same manner as in Example 1 using the salt (133 mg).

 'H-NMR (400MHz, CDC1) δ: 2.07 (4Η, m), 3.91 (2Η, m), 4. 15 (2H,

 Three

m), 4.19 (3H, s), 6.20 (1H, dt, J = 2.69, 1.59Hz), 6.75 (1H, dd, J = 4. 76, 2.69Hz), 6.85 (1H, s), 7.04 (IH, dt, J = 2.81, 1.83Hz), 7.09 (1H

, d, J = 9.28Hz), 7.55 (1H, d, J = 9.28Hz), 8.34 (1H, br).

 FAB MSm / z: 389 (M + H) +.

[0700] [Example 59] 1— [1— (6-Methoxy-3 pyridazil) -5- (1H-pyrrole 3-yl) —1H Pyrazole-3-carbol] -4-methoxy pipette Lysine

[0701] [Chemical 147]

[0702] Reference Example 33 1 (6-methoxy-3-pyridazil) -5- (1H-pyrrole-3-yl) -1H pyrazole-3-carboxylic acid (200 mg) and Reference Example 23 4-methoxypipe The title compound (177 mg, 66%) was obtained as an amorphous product in the same manner as in Example 1 using lysine hydrochloride (128 mg).

 'H-NMR (400MHz, CDCl) δ: 1.66 (2Η, m), 1.93 (2Η, m), 3.37 (3H,

 Three

 s), 3.50 (2H, m), 3.67 (1H, m), 4.10 (1H, m), 4.18 (3H, s), 4.24 (IH

, m), 6.19 (1H, d, J = l.47Hz), 6.74 (IH, dd, J = 4.76, 2.69Hz), 6.78

(IH, s), 7.04 (IH, s), 7.08 (IH, d, J = 9.28Hz), 7.60 (1H, d, J = 9.28

Hz), 8.52 (IH, br).

 FAB MSm / z: 383 (M + H) +.

[0703] [Example 60] 1— [1— (6-Methoxy-3-pyridyl) -5- (1-methyl-1H-pyrrole 3-yl) 1H-pyrazole-3-carbol] -4-methyl 3 —Oxopipera Gin

[0704] [Chemical 148]

[0705] Reference Example 32 1- (6-Methoxy-1-pyridyl) 5-- (1-Methyl 1H pyrrole 3-yl) -1H-pyrazole-3-strong rubonic acid (250 mg) and 1-methylbiperazine of Reference Example 46 — The title compound (159 mg, 45%) was obtained as an amorphous product in the same manner as in Example 1 using 2-one (115 mg).

 'H-NMR (400MHz, CDCl) δ: 3.01 (3Η, s), 3.46 (2Η, t, J = 5.49Hz),

 Three

 3.60 (3H, s), 3.99 (3H, s), 4.02 (1.5H, m), 4.42 (1.5H, br), 4.81 (1

H, br), 5.91 (1H, s), 6.46 (1H, br), 6.51 (1H, t, J = 2.44Hz), 6.80 (2

H, m), 7.64 (1H, m), 8.24 (1H, s).

 FAB— MSm / z: 395 (M + H) +.

[Example 61] 4- [5- (2-Methyloxazole-4-yl) -1-1- (6-Methyl-3-pyridyl) -1H-pyrazole 3-carbol] morpholine

[0707] [Chemical 149]

参考例 45の 5—（2—メチルォキサゾールー 4 ィル） 1一（6—メチルー 3 ピリ ジル） 1H ピラゾールー 3—カルボン酸（95.9mg)とモルホリン（0.0673ml)と を用いて、実施例 1と同様の方法で、標題化合物（7.4mg, 0.2%)を油状物として 得た。

Using Reference Example 45, 5- (2-methyloxazole-4-yl) 1 (6-methyl-3-pyridyl) 1H pyrazole-3-carboxylic acid (95.9 mg) and morpholine (0.0673 ml) In the same manner as in Example 1, the title compound (7.4 mg, 0.2%) was obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 2.44 (3Η, s), 2.64 (3Η, s), 3.65—3.85

 Three

(6H, m), 4.08 (2H, br), 7.08 (1H, s), 7.23— 7.32 (2H, m), 7.70 (1H, dd, J = 8.3, 2.7Hz), 8.56 (1H, d, J = 2.7Hz). FAB MSm / z: 354 (M + H) +.

[0709] [Example 62] (2S) 1 [5- (1-Methyl- 1H pyrrole 3 yl) 11 (6-Methyl 3 pyridazil) 1H Pyrazole 3 carbonyl] 2 Fluoromethyl pyrrolidine

 [0710] [Chemical 150]

[0711] Reference Example 36, 5— (1-Methyl-1H pyrrole-3-yl) -1-1- (6-Methyl-3-pyridazil) 1H Pyrazole-3-strong rubonic acid (0.244 g) and Reference Example The title compound (0.203 g, 64%) was obtained in the same manner as in Example 1 using 27 (2S) -2 fluoromethylpyrrolidine hydrochloride (0.180 g).

 'H-NMR (400MHz, CDC1) δ: 1.85— 2.19 (4Η, m), 2.78 (3Η, s), 3.6

 Three

 0-3.82 (1ΗΧ2 / 3, m), 3.63 (3H, s), 3.96—4.07 (1H + 1HX 1/3, m), 4.32-4.8K2H + 1HX2 / 3, m), 5.07—5.22 (lHXl / 3, m), 6.12— 6. 18 (1H, m), 6.53— 6.57 (1H, m), 6.90— 7.03 (2H, m), 7.42— 7.50 (1H, m), 7.64-7.69 (1H, m ).

 ESI— MSm / z: 369 (M + H) +.

[0712] [Example 63] 1— [5— (1-Methyl-1H-pyrrolidyl 3-yl) 1 (6-Methyl-3 pyridazil) 1H Pyrazole-3 carbol] —3, 3 Difluoro Azetidin

 [0713] [Chemical 151]

[0714] 参考例 36の 5—（1ーメチルー 1H—ピロ一ルー 3—ィル）ー1 （6—メチルー 3— ピリダジ-ル）— 1H ピラゾールー 3—カルボン酸（0.248g)と 3, 3 ジフルォロア ゼチジン塩酸塩（0. 173g, C. W. Robertら， MERCK SHARP & DOHME LIMITED, WO00Z47582)を用いて、実施例 1と同様の方法で、標題化合物（0 .243g, 78%)を固体として得た。

[0714] Reference Example 36 5- (1-Methyl-1H-Pyrroyl 3-yl) -1 (6-Methyl-3-pyridazil)-1H Pyrazole-3-carboxylic acid (0.248 g) and 3, 3 difluoro The title compound (0.243 g, 78%) was obtained as a solid in the same manner as in Example 1 using zetidine hydrochloride (0.173 g, CW Robert et al., MERCK SHARP & DOHME LIMITED, WO00Z47582).

 'H-NMR (400MHz, CDC1) δ: 2.80 (3Η, s), 3.62 (3Η, s), 4.51 (2H, t

 Three

 , J = 12.0Hz), 4.91 (2H, t, J = 12.0Hz), 6.05—6.12 (1H, m), 6.50—6

.54 (1H, m), 6.90— 6.96 (1H, m), 6.97 (1H, s), 7.47 (1H, d, J = 8.8H z), 7.61 (1H, d, J = 8.8Hz).

 FAB— MSm / z: 359 (M + H) +.

[0715] [Example 64] 1- [1 (6-Methoxy-3 pyridazil) -5- (2 pyridyl) 1H-pyrazole-3-carbonyl] -3,3-difluoroazetidine

[0716] [Chemical 152]

 Reference Example 1 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) -1H Pyrazo 1-Lu 3-Strength rubonic acid (0.254 g) and 3, 3 Difluoroazetidine hydrochloride (0.168 g, CW Robert et al., MERCK SHARP & DOHME LIMITED, WOOO / 475 82), and the title compound (0.232 g, 73%) was obtained as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 4.12 (3Η, s), 4.54 (2Η, t, J = ll.9Hz),

 Three

 4.94 (2H, t, J = ll.9Hz), 7.15 (1H, d, J = 9.0Hz), 7.20— 7.35 (2H, m), 7.61 (1H, d like, J = 7. 1Hz), 7.73— 7.82 (2H, m), 8.38 (1H, d like, J = 4.9Hz).

FAB MSm / z: 373 (M + H) +. [0718] [Example 65] 1— [1— (6-Methoxy-3-pyridyl) 5— (2 pyrajur) 1H-Pyrazole 3-carbonyl] 4 Methyl 3-oxopiperazine

[0719] [Chemical 153]

 Reference Example 6 1- (6-Methoxy-1-pyridyl) -5- (2 Pyraduryl) -1-H Pyrazo One-Loo 3-Strong Rubonic Acid (0.23 lg) and 1-Methylbiperazine 2-one of Reference Example 46 (0 In the same manner as in Example 1, the title compound (0.252 g, 78%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.03 (3Η, s), 3.46—3.50 (2Η, m), 3.9

Three

 7 (3H, s), 4.04-4.07 (1H, m), 4.41—4.45 (2H, m), 4.84 (1H, br s),

6.80 (1H, d, J = 8.8Hz), 7.31— 7.36 (1H, m), 7.56— 7.65 (1H, m), 8.

09-8.15 (1H, m), 8.47- 8.52 (2H, m), 8.72- 8.75 (1H, m).

 ESI MSm / z: 394 (M + H) +.

[0720] [Example 66] 1— [1- (6-Methoxy-3-pyridyl) -5- (1H pyrazole-3-yl) 1H-pyrazole-3-carbol] -4-methoxypiperidine

[0721] [Chemical 154]

参考例 13の 1— (6—メトキシ— 3 ピリジル）—5— (1H ピラゾール— 3—ィル） — 1H ピラゾールー 3—カルボン酸（0.370g)と参考例 23の 4—メトキシピぺリジン 塩酸塩 (0.359g)とを用いて、実施例 1と同様の方法で、標題化合物（0.222g, 43 %)をアモルファスとして得た。

Reference Example 13 1- (6-Methoxy-3 pyridyl) -5- (1H pyrazole-3-yl) — 1H Pyrazole-3-carboxylic acid (0.370 g) and 4-methoxypiperidine hydrochloride of Reference Example 23 ( 0.359 g) and the title compound (0.222 g, 43 %) Was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 1.61— 1.74 (2Η, m), 1.89—2.00 (2Η,

 Three

 m), 3.38 (3H, s), 3.47-3.58 (2H, m), 3.72—3.79 (1H, m), 3.97 (3H, s), 4.07-4.13 (1H, m), 4.27—4.33 (1H, m), 6.12 (1H, d, J = 2.2Hz), 6.79 (1H, d, J = 8.8Hz), 7.19 (1H, s), 7.53 (1H, d, J = 2.4Hz), 7.64 (1H, dd, J = 8.8, 2.7Hz), 8.24 (1H, d, J = 2.4Hz).

 ESI— MSm / z: 383 (M + H) +.

 [0723] [Example 67] 1— [1 (6-Methoxy-3-pyridazil) -5- (5-methyl-2-pyrazyl-)-1H pyrazole-3-carbol] — 4, 4 Difluoropiperidine

 [0724] [Chemical 155]

[0725] Reference Example 47-1 (6-methoxy-3-pyridazil) -5- (5-methyl-2-pyrazole)-1H-pyrazole-3-carboxylic acid (0.30 g) and Reference Example 18, 4, 4 difluoropiperidine The title compound (0.3 14 g, 79%) was obtained as a solid in the same manner as in Example 1 using hydrochloride (0.182 g).

 'H-NMR (400MHz, CDC1) δ: 2.08— 2.09 (4Η, m), 2.59 (3Η, s), 3.9

 Three

 2-3.94 (2H, m), 4.09—4. 19 (2H, m), 4.12 (3H, s), 7.17— 7.19 (2H, m), 7.84 (1H, d, J = 9.3Hz), 8.29— 8.30 (1H, m), 8.70 (1H, d, J = l.5Hz).

 EI-MSm / z: 415 (M +).

[Example 68] 4- [1 (6- (Methyl-3-pyridyl) 5- (5-Methyl-2-pyridyl)]

 -1H pyrazole-3-carbol] morpholine

[0727] [Chemical 156]

[0728] Using Reference Example 48 1- (6-Methyl-3 pyridyl) -5- (5-methyl-2 pyridyl) 1 H pyrazole-3-carboxylic acid (0.245 g) and morpholine (0.109 ml) In the same manner as in Example 1, the title compound (0.228 g, 75%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.34 (3Η, s), 2.59 (3Η, s), 3.73— 3.83

 Three

 (6H, m), 4.14 (2H, m), 7.11 (1H, s), 7.19 (1H, d, J = 8.4Hz), 7.33 (1 H, d, J = 8.0Hz), 7.51-7.53 (1H, m), 7.61— 7.64 (1H, m), 8.33— 8. 38 (2H, m).

 ESI MSm / z: 364 (M + H) +.

[0729] [Example 69] 1— [1— (6-Methoxy-1-pyridyl) 5— (1-Methyl 1H— 1, 2, 4 Triazole-3 yl) 1H Pyrazole-3 carb] —4, 4 Difluoro piperidine

[0730] [Chemical 157]

参考例 49の 1— (6—メトキシ一 3 ピリジル） 5— (1—メチル 1H—1, 2, 4 ト リアゾール—3—ィル） 1H ピラゾールー 3—カルボン酸ェチルエステル（68mg) のテトラヒドロフラン（10ml)と水（5ml)の混合溶液に、水酸化リチウム一水和物（26 mg)を室温で加え終夜攪拌した。反応液溶媒を減圧下で留去し、 1— (6—メトキシ — 3 ピリジル） 5— (1—メチル 1H— 1, 2, 4 トリァゾール— 3—ィル）—1H— ピラゾールー 3—力ルボン酸リチウム塩を得た。このリチウム塩、参考例 18の 4, 4 ジフルォロピペリジン塩酸塩（65mg)、 1—ヒドロキシベンゾトリアゾール（28mg)、トリ ェチルァミン（144 μ 1)および 3—（3 ジメチルァミノプロピル） 1 ェチルカルボジ イミド塩酸塩（79mg)のジクロロメタン（20ml)と Ν, N ジメチルホルムアミド（10ml) 混合溶液を室温で終夜攪拌した。反応液の溶媒を減圧下で留去し得られた残渣を シリカゲル薄層クロマトグラフィー (メタノール一クロ口ホルム)で精製し、標題化合物（ 46mg, 55%)をアモルファスとして得た。

1- (6-Methoxy-3-pyridyl) of Reference Example 49 5- (1-Methyl 1H-1,2,4 triazole-3-yl) 1H Pyrazole-3-carboxylic acid ethyl ester (68 mg) in tetrahydrofuran (10 ml) Lithium hydroxide monohydrate (26 mg) was added to a mixed solution of water and water (5 ml) at room temperature and stirred overnight. The reaction solution was evaporated under reduced pressure to give 1— (6-methoxy-3-pyridyl) 5— (1-methyl 1H— 1, 2, 4 triazole-3-yl) —1H—pyrazole-3-strong rubonic acid A lithium salt was obtained. This lithium salt, Reference Example 18, 4, 4 Difluoropiperidine hydrochloride (65 mg), 1-hydroxybenzotriazole (28 mg), tritylamine (144 μ 1) and 3- (3 dimethylaminopropyl) 1-ethylcarbodiimide hydrochloride (79 mg) in dichloromethane (20 ml) A mixed solution of N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (methanol / chloroform form) to obtain the title compound (46 mg, 55%) as an amorphous product.

 'H-NMR (400MHz, CDC1) δ: 2.08 (4Η, br s), 3.90 (5H, s), 3.98 (3H

 Three

 , s), 4.16 (2H, s), 6.81 (1H, d, J = 8.5Hz), 7.30 (1H, s), 7.70 (1H, dd

, J = 8.9, 2.6Hz), 7.99 (1H, s), 8.23 (1H, d, J = 2.7Hz).

 ESI-MSm / z: 404 (M + H) +.

[0732] [Example 70] (2S) -1 [1 (6-Methoxy-3 pyridyl) -5- (2 pyrajur)

1H-Pyrazole 3 Carbon] 2 Fluoromethylpyrrolidine

[0733] [Chemical 158]

[0734] Reference Example 6 1- (6-Methoxy-1-pyridyl) 5-- (2 Pyrazyl) 1H Pyrazo One-Lou 3-Strength Rubonic Acid (297 mg) and Reference Example 27 (2S) — 2 Fluoro The title compound (140 mg, 37%) was obtained as a solid in the same manner as in Example 5 using methylpyrrolidine hydrochloride (140 mg).

 'H-NMR (400MHz, CDC1) δ: 1.59— 2.08 (4Η, m), 3.70— 5.19 (5Η,

 Three

 m), 3.97 (3H, s), 6.77 and 6.80 (1H, s), 7.37 and 7.40 (1H, s), 7.57-7.62 (1H, m), 8.11-8.14 (1H, m), 8.46- 8.52 (2H, m), 8.75 and 8.77 (1H, s in total).

 ESI— MSm / z: 383 (M + H) +.

[0735] [Example 71] (2S) — 1 [1 (6-methoxy-3-pyridazil) 5— (2 pyrajur ) — 1H Pyrazole-3 Power Lolol] — 2 Fluoromethylpyrrolidine

[0736] [Chemical 159]

[0737] Reference Example 12 1- (6-Methoxy-3 pyridazil) -5- (2 Pyrazil) 1H Pyrazole 3-Strong rubonic acid (298 mg) and Reference Example 27 (2S) -2 Full The title compound (166 mg, 43%) was obtained as a solid in the same manner as in Example 5 using o-methylpyrrolidine hydrochloride (140 mg).

 'H-NMR (400MHz, CDC1) δ: 1.95— 2.17 (4Η, m), 3.72— 5.20 (5Η,

 Three

 m), 4.11 (3H, s), 7.17 and 7.19 (total 1H, d, J = 9.2Hz), 7.32 an d 7.37 (total 1H, s), 7.87 and 7.89 (total 1H, d, J = 9.2Hz), 8. 42-8.44 (1H, m), 8.52-8.54 (1H, m), 8.85 and 8.86 (1H, d, J = l.2Hz in total).

 ESI MSm / z: 384 (M + H) +.

[0738] [Example 72] 1— [1— (6-Methoxy-3-pyridyl) -5- (1H-pyrrole 3-yl)

 1H pyrazole-3 carbonyl] -4-methoxypiperidine

[0739] [Chemical 160]

参考例 32の 1— (6—メトキシ— 3 ピリジル） -5- (1H ピロール— 3—ィル） 1 H ピラゾールー 3—力ルボン酸（200mg)と参考例 23の 4ーメトキシピペリジン塩酸 塩（160mg)とを用いて、実施例 1と同様の方法で、標題ィ匕合物（130mg, 48%)を アモルファスとして得た。

1- (6-Methoxy-3-pyridyl) -5- (1H pyrrole-3-yl) in Reference Example 32 1-Hyperazole-3-strong rubonic acid (200 mg) and 4-methoxypiperidine hydrochloride (160 mg in Reference Example 23) ) To give the title compound (130 mg, 48%) in the same manner as in Example 1. Obtained as amorphous.

^X H-NMR (400MHz, CDCl) δ: 1.67 (2H, m), 1.94 (2H, m), 3.38 (3H,

 Three

 s), 3.49 (2H, m), 3.72 (1H, m), 3.98 (3H, s), 4.10 (IH, br), 4.29 (IH, br), 6.04 (IH, dt, J = 2.69, 1.59Hz), 6.64 (1H, dt, J = 2.69, 1.83Hz), 6.73 (1H, dd, J = 4.26, 2.69Hz), 6.77 (1H, s), 6.79 (IH, d, J = 8.79 Hz) , 7.61 (IH, dd, J = 8.79, 2.69Hz), 8.24 (IH, d, J = 2.08Hz), 8.39 (IH, br).

 FAB MSm / z: 382 (M + H) +.

[0741] [Example 73] 1— [1— (6-Methoxy-3-pyridyl) -5- (1-methyl-1H-imidazo 1-ru 4-yl) -1H pyrazole 3-carbol] -4-methoxypipe Lysine

[0742] [Chemical 161]

[0743] 1- (6-Methoxy-1-pyridyl) of Reference Example 34 5- (1-Methyl 1H-imidazole 4-yl) 1H Pyrazole 3 carboxylic acid (150 mg) and 4-Methoxypiperidine of Reference Example 23 The title compound (133 mg, 67%) was obtained as a solid in the same manner as in Example 5 using hydrochloride (91 mg).

 'H-NMR (400MHz, CDCl) δ: 1.65 (2Η, br s), 1.93 (2H, br s), 3.36

 Three

 (3H, s), 3.46-3.50 (2H, m), 3.65 (4H, s), 3.97 (3H, s), 4.09 (1H, br s), 4.23 (IH, br s), 6.68 (IH, d , J = l.2Hz), 6.79 (1H, d, J = 8.8Hz), 6.93 (1H, s), 7.40 (1H, s), 7.70 (1H, dd, J = 8.8, 2.7Hz), 8.24 ( IH, d, J = 2.7Hz).

ESI-MSm / z: 397 (M + H) ⁺ .

[Example 74] 1- [1 (6-Methoxy-3 pyridazil) -5- (1H-pyrrole 3-yl) 1H Pyrazole-3 carbol] -4-methylbiperazine [0745] [Chemical 162]

[0746] Reference Example 33-1 (6-methoxy-3-pyridazil) -5- (1H-pyrrole-3-yl)-1 H pyrazole 3 carboxylic acid (200 mg) and N-methylbiperazine (116 1) In the same manner as in Example 1, the title compound (86 mg, 30%) was obtained as amorphous.

 'H-NMR (400MHz, CDC1) δ: 2. 32 (3Η, s), 2. 43 (2Η, br), 2. 50 (2H,

 Three

 br), 3. 84 (2H, br), 4. 05 (2H, br), 4. 18 (3H, s), 6. 19 (IH, s), 6. 74 (IH

, dd, J = 4.64, 2.69Hz), 6.81 (IH, s), 7.03 (1H, s), 7.08 (IH, d, J = 9.

16Hz), 7.58 (IH, d, J = 9.16Hz), 8.45 (IH, br).

 FAB MSm / z: 368 (M + H) +.

[0747] [Example 75] 4— [5— (3—Strength of ruber moyl IH—Pyrroyl 1 l) —1— (6-Methoxy-3-pyridyl) -1H-pyrazole 3 carbol] morpholine

[0748] [Chemical 163]

参考例 52の 5—（3—力ルバモイルー 1H—ピロ一ルー 1ーィル） 1 （6—メトキシ —3 ピリジル）—1H ピラゾールー 3—カルボン酸ェチルエステル（0. 123g)のェ タノール（5ml)とテトラヒドロフラン（5ml)混合溶液に、室温で 1N水酸ィ匕ナトリウム水 溶液（1. 00ml)を加え 5. 5時間攪拌した。反応液に 1N塩酸水溶液（1. 00ml)を加 えた後、反応溶媒を減圧下留去し 5—（3—力ルバモイルー 1H—ピロ一ルー 1ーィル )—1— (6—メトキシ一 3 ピリジル） 1H ピラゾール一 3—カルボン酸を得た。こ のカルボン酸とモルホリン（55.0 1)とを用いて、実施例 1と同様の方法で、標題ィ匕 合物（98. Omg, 69%)を固体として得た。

Reference Example 52 5- (3-Strength Rubamoyl 1H-Pyrroyl 1-yl) 1 (6-Methoxy-3 pyridyl) -1H Pyrazole 3-Carboxylic acid ethyl ester (0.123 g) Ethanol (5 ml) and tetrahydrofuran ( To the mixed solution, 1N aqueous sodium hydroxide solution (1.00 ml) was added at room temperature, and the mixture was stirred for 5.5 hours. Add 1N aqueous hydrochloric acid (1.00 ml) to the reaction mixture. After that, the reaction solvent was distilled off under reduced pressure to obtain 5- (3-force rubamoyl-1H-pyrrole-1-yl) -1- (6-methoxy-1-pyridyl) 1H-pyrazole-3-carboxylic acid. Using this carboxylic acid and morpholine (55.0 1), the title compound (98. Omg, 69%) was obtained as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 3.74— 3.83 (6Η, m), 3.95 (3Η, s), 4.1

 Three

 6-4.19 (2H, m), 5.55 (2H, br s), 6.53 (1H, dd, J = 2.9, 1.7Hz), 6.6 6 (1H, dd, J = 3.1, 2.3Hz), 6.74 ( 1H, d, J = 8.8Hz), 6.91 (1H, s), 7.2 6-7.27 (1H, m), 7.32 (1H, dd, J = 8.9, 2.8Hz), 8.02 (1H, d, J = 2.4 H z).

ESI-MSm / z: 397 (M + H) ⁺ .

[0750] [Example 76] 1— [1— (6-Methoxy-3-pyridyl) -5- (1H-pyrrole 3-yl)

 1H Pyrazole-3 Carbonyl]-2-Power Rubamoylpyrazolidine

[0751] [Chemical 164]

1) 1— [1— (6-Methoxy-1-pyridyl) -5- (1H pyrrole 3-yl) 1H pyrazole 3-carbonyl] 2- tert-butoxycarbonylpyrazolidine

 Reference Example 30 1- (6-Methoxy-3 pyridyl) -5- (1H pyrrole-3-yl) -1 H pyrazole-3-strong rubonic acid (0.444 g) and virazolidine 1 monostrength rubonic acid tert-butyl ester (0.403 g, Y. Endo et al., Bioorg. Med. Chem., 2002, 10, 953) and 1 [1- (6-methoxy-3-pyridyl) -5 — (1ΗPyrrole-3 yl) 1H Pyrazole-3 carb] — 2-tert-butoxy carborpyrazolidine (566 mg, 82%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.42 (9Η, s), 2.11 (2Η, br s), 3.25 (1H

 Three

, br s), 3.49 (1H, br s), 3.97 (3H, s), 4.10 (1H, br s), 4.35 (1H, br s ), 6.02-6.04 (IH, m), 6.60 (1H, br s), 6.71— 6.73 (1H, m), 6.77 (1 H, d, J = 8.5Hz), 6.88 (1H, br s), 7.64 (1H, dd, J = 8.8, 2.7Hz), 8.23 (IH, d, J = 2.2Hz), 8.38 (IH, br s).

ESI-MSm / z: 439 (M + H) ⁺ .

[0753] 2) 1— [1— (6-Methoxy-1-pyridyl) 5-— (1H-pyrrole-3-yl) 1H-pyrazole 3-carbol] pyrazolidine

 1- [1- (6-Methoxy-1-pyridyl) 5- (1H-pyrrole-3-yl) 1H-pyrazole-3 carbol] -2-tert-butoxycarbol-pyrazolidine (0.549 g) In the same manner as 6-2, 1 [1- (6-Methoxy-3-pyridyl) -5- (1H pyrrole-3-yl) -1H pyrazole-3-carbol] virazolidine (37 8mg, 89% ) Was obtained as amorphous.

 'H-NMR (400MHz, CDCl) δ: 2.14 (IH, br s), 2.23 (IH, br s), 3.16

 Three

 -3.20 (2H, m), 3.80 (1H, br s), 3.97 (3H, s), 4.14 (1H, br s), 4.92 (IH, br s), 6.04-6.06 (IH, m), 6.63 ( 1H, br s), 6.71— 6.73 (1H, m), 6.77 (1H, d, J = 8.8Hz), 6.95 (1H, s), 7.62— 7.66 (1H, m), 8.26 (1H, d, J = 2.2Hz), 8.33 (IH, br s).

 ESI— MSm / z: 339 (M + H) +.

[0754] 3) Title compound

 1— [1— (6-Methoxy-1-pyridyl) -5- (1H-pyrrole-1-yl) 1H-pyrazole-3-carbol] virazolidine (0.378 g) in 1,4-dioxane (2.5 ml) Then, trimethylsilyl isocyanate (1.77 ml) was added at room temperature, and the mixture was stirred for 3 hours at 115 ° C in the sealed tube. After air cooling, methanol was added to the reaction solution, and the reaction solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-dichloromethane) to give the title compound (280 mg, 65%) as a solid. Got as.

 'H-NMR (400MHz, DMSO-d) δ: 1.93—2.00 (2Η, m), 3.30 (2Η, br

 6

s), 3.92 (3H, s), 5.86— 5.88 (2H, m), 6.65— 6.66 (2H, m), 6.73— 6.75 (1H, m), 6.81 (IH, s), 6.94 (IH, d, J = 8.5Hz), 7.75 (1H, dd, J = 8.8, 2.7Hz), 8.22 (1H, d, J = 2.2Hz), 11.05 (1H, br s). ESI-MSm / z : 382 (M + H) +.

 [0755] [Example 77] 1— [1— (6-Methoxy-3-pyridyl) -5- (1H pyrazole-3-yl) -1-H pyrazole 3 carbonyl] 4 methyl 3oxopiperazine

[0756] [Chemical 165]

[0757] Reference Example 13 1- (6-Methoxy-1-pyridyl) 5-- (1H Pyrazole 3-yl)

 The title compound (1H) was prepared in the same manner as in Example 1 using 1-pyrazole-3-strong rubonic acid (0.393 g) and 1-methylbiperazin-2-one (0.469 g) of Reference Example 46. 217 mg, 38%) was obtained as amorphous.

 'H-NMR (400MHz, CDCl) δ: 3.02 (3Η, s), 3.46—3.49 (2Η, m), 3.9

 Three

8 (3H, s), 4.03-4.07 (1H, m), 4.44 (2H, br s), 4.84 (1H, br s), 6.1 5 (1H, br s), 6.80 (1H, d, J = 9.0 Hz), 7.23 (1 / 2H, br s), 7.31 (1 / 2H, br s), 7.54 (1H, br s), 7.60— 7.67 (1H, m), 8.20— 8.26 (1H, m) .ESI -MSm / z: 382 (M + H) ⁺ .

 [Example 78] [0758] 1— [5- (2-Methyl-1H imidazole-4-yl) 1 1 (6-methoxy-3-pyridyl) 1H pyrazole-3-carbol] -4-methoxypiperidine

[0759] [Chemical 166]

Ethanol of Reference Example 51 5- (2-Methyl-1H-imidazole-4-yl) 1 (6-methoxy-3-pyridyl) -1H pyrazole-3-carboxylic acid ethyl ester (0.353 g) IN aqueous sodium hydroxide solution (3.50 ml) was stirred at room temperature for 3 hours in a solution of nor (10 ml). To the reaction solution was added 1N aqueous hydrochloric acid solution (3.50 ml), and the solvent of the reaction solution was evaporated under reduced pressure. 5- (2-Methyl-1H-imidazole-4-yl) -1- (6-methoxy-3-pyridyl) 1H pyrazole 3-Strong rubonic acid was obtained. Using this carboxylic acid form and 4-methoxypiperidine hydrochloride (0.293 g) of Reference Example 23, the title compound (0.193 g, 45%) was obtained as an amorphous form in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 1.60—1.73 (2Η, m), 1.86— 1.98 (2Η,

 Three

 m), 2.35 (3H, s), 3.37 (3H, s), 3.46—3.57 (2H, m), 3.65—3.72 (1H, m), 3.96 (3H, s), 4.02—4.08 (1H, m) , 4.15—4.22 (1H, m), 6.49 (1 H, s), 6.78 (1H, d, J = 8.8Hz), 6.89 (1H, s), 7.62 (1H, dd, J = 8.8, 2.7Hz ), 8.21 (1H, d, J = 2.7Hz).

ESI-MSm / z: 397 (M + H) ⁺ .

 [0761] [Example 79] 1— [5— (5 amino-2-pyrazuryl) -1- 1- (6-methoxy-1-pyridyl) 1- 1H pyrazole-3 carbol] -4 fluoropiperidine

 [0762] [Chemical 167]

1) 1— [5— (5— tert-Butoxycarbo-lamino- 2 pyrajur) — 1— (6-Methoxy-3-pyridyl) —1H Pyrazole- 3-carbol] —4 Fluoropiperidine Reference Example 42 5- (5-tert-butoxycarbolamino 2 pyridyl) -1 (6-methoxy-1-pyridyl) 1H pyrazole-1-3-carboxylic acid (0.200 g) and 4 fluoropiperidine hydrochloride (0. 135g) in the same manner as in Example 1,

[5- (5-tert-butoxycarbolamino 2 pyridyl) 1 (6-methoxy-3-pyridyl) -1H pyrazole-3-carbol] — 4 fluoropiperidine (0.23 Og, 95%) was obtained as a solid . NMR-NMR (400MHz, CDCl) δ: 1.54 (9H, s), 1.92—1.99 (4H, m), 3.7

 Three

 0-4.08 (3H, m), 3.97 (3H, s), 4.21—4.25 (1H, m), 4.86—4.99 (1H, m), 6.77 (1H, d, J = 8.8Hz), 7.13 (1H, s), 7.45 (1H, s), 7.60 (1H, dd, J = 8.8, 2.7Hz), 8.12 (1H, d, J = 2.7Hz), 8.33 (1H, d, J = l.5Hz), 9 17 (1H, d, J = l.5Hz).

EI-MSm / z: 497 (M ⁺ ).

[0764] 2) Title compound

 1 1 [5- (5-tert-Butoxycarbolamino 2 Pyradol) 1 1 1 (6-Methoxy-3 pyridyl) -1H pyrazole 3-carbol] -4 With fluoropiperidine (0.225 g) In the same manner as in Example 56, 2), the title compound (0.117 g, 65%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.92—1.99 (4Η, m), 3.70 (IH, m), 3.

 Three

 92-4.07 (2H, m), 3.96 (3H, s), 4.20—4.23 (1H, m), 4.81 (2H, br s), 4.85-4.99 (1H, m), 6.77 (1H, d, J = 8.8Hz), 7.03 (1H, s), 7.60 (1H, dd, J = 8.8, 2.7Hz), 7.88 (1H, s), 8.10 (1H, s), 8.14 (1H, d, J = 2.7 Hz) .

EI-MSm / z: 397 (M ⁺ ).

[0765] [Example 80] 1— [5 -— (5-Amino-2-pyriduryl) 1 (6-methoxy-3-pyridyl)

)-1H Pyrazole 3-Carbon] —4-Methoxypiperidine

[0766] [Chemical 168]

1) 1— [5— (5— tert-Butoxycarbo-lamino- 2 pyraduryl) — 1— (6-Methoxy-1-pyridyl) 1H pyrazole- 3-carbol] —4-methoxypiperidine Reference Example 42 5— (5— tert Butoxycarbolamino 2 pyrajur) -1 (6— Methoxy-1-pyridyl) 1H Pyrazole-1-3-carboxylic acid (0.200 g) and 4-methoxypiperidine hydrochloride (0.147 g) of Reference Example 23 were used in the same manner as in Example 1,

 [5- (5-tert-Butoxycarbolamino 2 pyridyl) 1 (6-methoxy-3-pyridyl) 1H pyrazole-3-carbol] -4-methoxypiperidine (0.211 g, 85%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.54 (9Η, s), 1.69— 1.86 (4Η, m), 3.3

 Three

 8 (3H, s), 3.47-3.57 (2H, m), 3.72— 3.78 (1H, m), 3.96 (3H, s), 4.09 (1H, m), 4.26 (1H, m), 6.77 ( 1H, d, J = 8.8Hz), 7.11 (1H, s), 7.38 (1H, s), 7.61 (1H, dd, J = 8.8, 2.7Hz), 8.11— 8.12 (1H, m), 8.32 (1H , d, J = l.5Hz), 9.16 (1H, d, J = l.5Hz).

 EI— MSmZz: 509 (M +).

[0768] 2) Title compound

 1 1 [5- (5-tert-butoxycarbolamino 2 pyridyl) 1 1 1 (6 methoxy 3 pyridyl) 1H pyrazole 3-carbol] 4 Conducted with 4-methoxypiperidine (0.2 06 g) In the same manner as in Example 56, 2), the title compound (0.125 g, 75%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.67—1.94 (4Η, m), 3.38 (3Η, s), 3.4

 Three

 5-3.55 (2H, m), 3.71— 3.75 (1H, m), 3.95 (3H, s), 4.09 (1H, m), 4.

28 (1H, m), 4.81 (2H, br s), 6.77 (1H, d, J = 8.8Hz), 7.00 (1H, s), 7.

61 (1H, dd, J = 8.8, 2.7Hz), 7.87—7.88 (1H, m), 8.09 (1H, d, J = l.5

Hz), 8.14 (1H, d, J = 2.7Hz).

EI-MSm / z: 409 (M ⁺ ).

[Example 81] 1— [5— (5 Amino-2-pyrazuryl) -1- (6-methoxy-1-3pyridyl]

)-1H pyrazole-3-carbol]-4-methylbiperazine

[0770] [Chemical 169]

[0771] 1) 1 [5— (5-tert-Butoxycarbolamino 2 Pyradur) 1 (6-Methoxy-3-pyridyl) 1H Pyrazole-3-Carbol] -4-Methylbiperazine Reference Example 42 5— (5 — Tert-Butoxycarbolamino 2 Pyradur) -1 (6-Methoxy-1-pyridyl) 1H Pyrazole-1-3-carboxylic acid (0.200 g) and N-methylpiperazine (0.108 ml) as in Example 1 1— [5— (5— tert-butoxycarbo-lamino-1 pyridyl) 1 1— (6-methoxy-1-pyridyl) 1H —pyrazole-3-carbol] —4-methylbiperazine (0.146 g, 61%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.54 (9Η, s), 2.34 (3Η, s), 2.48—2.53

 Three

(4H, m), 3.86 (2H, m), 3.96 (3H, s), 4.12 (2H, m), 6.77 (1H, d, J = 8.8Hz), 7.14 (1H, s), 7.39 (1H, s), 7.61 (1H, dd, J = 8.8, 2.7Hz), 8. 11 (1H, d, J = 2.7Hz), 8.32 (1H, d, J = l.5Hz), 9.16 (1H , d, J = l.5Hz) .EI-MSm / z: 494 (M ⁺ ).

[0772] 2) Title compound

 1 1 [5- (5-tert-Butoxycarbo-lumino 2-pyrazur) 1 1 1- (6-Methoxy-3 pyridyl) 1H pyrazole-3-carbol] —4-methylbiperazine (0.14 lg) was used in Example 56 The title compound (0.0799 g, 71%) was obtained as a solid by the same method as 2).

 'H-NMR (400MHz, CDCl) δ: 2.33 (3Η, s), 2.46—2.51 (4Η, m), 3.8

 Three

 5 (2H, m), 3.95 (3H, s), 4.09 (2H, m), 4.76 (2H, s), 6.75— 6.77 (1H, m), 7.02 (1H, s), 7.60 (1H, dd, J = 8.8, 2.7Hz), 7.86 (1H, d, J = l.5Hz), 8.09 (1H, d, J = l.5Hz), 8.12― 8.13 (1H, m).

EI-MSm / z: 394 (M ⁺ ). [Example 82] 1— [5— (5 amino-2-pyrazuryl) -1- (6-methoxy-1-pyridazi

-L) —1H pyrazole- 3-carbol] — 4, 4 difluoropiperidine

[0774] [Chemical 170]

[0775] 1) 1 [5— (5— tert Butoxycarbolamino 2 pyridyl) 1 (6—methoxy-3 pyridazil) 1H pyrazole 3 carbonyl] 4, 4 difluoropiperidine

 Reference Example 53, 5- (5-tert-butoxycarbolumino-2-pyrazur) -1 (6-methoxy-3-pyridazil) -1H pyrazole-3-carboxylic acid (0.350 g) and Reference Example 18, 4, 4-diflurane 1- [5— (5-tert-Butoxycarbolamamino 2 pyrajuryl) — 1— (6-Methoxy 3) Using olopiperidine hydrochloride (0.200 g) in the same manner as in Example 1. Pyridyl) 1H pyrazole 3 carbonyl] 4,4 difluoropiperidine (0.400 g, 92%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.54 (9Η, s), 2.09 (4Η, m), 3.93 (2H,

 Three

 m), 4.13 (3H, s), 4.17 (2H, m), 7.14 (1H, s), 7.17 (1H, d, J = 9.3Hz), 7.67 (1H, s), 7.80 (1H , d, J = 9.3Hz), 8.49 (1H, d, J = l.5Hz), 9.11 (1H, m).

EI-MSm / z: 516 (M ⁺ ).

[0776] 2) Title compound

 1 1 [5- (5-tert-Butoxycarbolamino 2 pyridyl) 1 1 1 (6-methoxy-3 pyridyl) -1H pyrazole-3-carbol] — 4, 4 Using difluoropiperidine (0.390 g) In the same manner as in Example 56 2), the title compound (0.268 g, 85%) was obtained as a solid.

'H-NMR (400MHz, CDCl) δ: 2.01— 2.10 (4Η, m), 3.78 (2Η, m), 4. 06 (2H, m), 4.06 (3H, s), 6.74 (2H, s), 7.09 (1H, s), 7.44 (IH, d, J = 9

.2Hz), 7.65 (1H, m), 7.94 (1H, d, J = 9.2Hz), 8.24 (IH, m).

ESI-MSm / z: 417 (M + H ⁺ ).

[0777] [Example 83] 1— [1 (6-methyl-3-pyridyl) 5- (5-methyl-2-pyridyl)

 -1H-pyrazole 3 carbonyl] 4 methyl 3oxopiperazine

[0778] [Chemical 171]

[0779] Reference Example 48 1- (6-Methyl-3 pyridyl) -5- (5-methyl-2 pyridyl) 1 H pyrazole-3-strength rubonic acid (0.245 g) and Reference Example 46 1-methylbipera The title compound (0.156 g, 48%) was obtained as a solid in the same manner as in Example 1 using gin 2 -one (0.285 g).

 'H-NMR (400MHz, CDCl) δ: 2.34 (3Η, s), 2.60 (3Η, s), 3.02 (3H, s)

 Three

 , 3.48 (2H, m), 4.05 (IH, m), 4.42—4.44 (2H, m), 4.84 (IH, m), 7.1

5-7.36 (3H, m), 7.51-7.72 (2H, m), 8.33-8.43 (2H, m).

 FAB— MSm / z: 391 (M + H +).

[0780] [Example 84] (2S) -1 [1 (6-Methyl-3 pyridyl) -5- (5-methyl-2-pyridyl) 1H pyrazole 3 carbonyl] -2-strength rubamoylpyrrolidine

[0781] [Chemical 172]

0, NH ₂

[0782] 参考例 48の 1— (6—メチル—3 ピリジル）—5— (5—メチル—2 ピリジル） 1 H ピラゾール一 3—カルボン酸（0.245g)と L プロリンアミド（0.190g)とを用い て、実施例 1と同様の方法で、標題化合物（0.182g, 56%)を固体として得た。 'H-NMR (400MHz, CDC1 ) δ :1.97— 2.46 (4Η, m), 2.34 (3Η, s), 2.5 0;

[0782] Reference Example 48 1- (6-Methyl-3 pyridyl) -5- (5-methyl-2 pyridyl) 1 H pyrazole mono 3-carboxylic acid (0.245 g) and L prolinamide (0.190 g) Was used to obtain the title compound (0.182 g, 56%) as a solid in the same manner as in Example 1. 'H-NMR (400MHz, CDC1) δ: 1.97— 2.46 (4Η, m), 2.34 (3Η, s), 2.5

 Three

 7-2.60 (3H, m), 3.84—4.20 (2H, m), 4.86— 5.30 (1H, m), 5.46— 5.53 (1H, m), 6.22— 7.04 (1H, m), 7.19— 7.24 (2H, m), 7.35-7.37 (1H, m), 7.52-7.55 (1H, m), 7.63-7.72 (1H, m), 8.25-8.40 (2H, m).

 ESI— MSm / z: 391 (M + H +).

[0783] [Example 85] 4- [1 (6-Methoxy-3 pyridazil) -5- (5-methyl-2 pyrazi

-L) 1H pyrazole 3 carbo] morpholine

[0784] [Chemical 173]

[0785] Reference Example 47-1 (6-methoxy-3-pyridazil) -5- (5-methyl-2-pyrazole) -1-H-pyrazole-1-3-carboxylic acid (0.250 g) and morpholine (0.105 ml) Thus, the title compound (0.157 g, 51%) was obtained as a solid in the same manner as in Example 1. 'H-NMR (400MHz, CDC1) δ: 2.58 (3Η, s), 3.72-3.84 (6Η, m), 4.0

 Three

 9-4.10 (2H, m), 4.12 (3H, s), 7. 16— 7.19 (2H, m), 7.84 (1H, d, J = 9

.2Hz), 8.29 (1H, m), 8.70—8.71 (1H, m).

ESI-MSm / z: 382 (M + H ⁺ ).

[Example 86] 4- [5- (5-Methoxyoxazol-2-yl) -1- (6-methyl-3-pyridyl) -1H-pyrazole 3 carbo] morpholine

[0787] [Chemical 174]

[0788] Reference Example 50 5- (5-Methoxyoxazole-2-yl) -1 (6-methyl-3-pyridyl) 1H pyrazole-3-carboxylic acid (14.9 mg) and morpholine (0.0150 ml) Was used to obtain the title compound (9.2 mg, 50%) as a solid in the same manner as in Example 1.

'H-NMR (400MHz, CDC1) δ: 2.65 (3Η, s), 3.66-3.85 (6Η, m), 3.9

 Three

 0 (3H, s), 4.10 (2H, br), 6.12 (1H, s), 7.25—7.32 (2H, m), 7.75 (1H, dd, J = 8.3, 2.7Hz), 8.63 (1H, d, J = 2.7Hz).

 ESI MSm / z: 370 (M + H) +.

[0789] [Example 87] (2R) — 1— [1— (6-Methoxy-3 pyridazil) -5- (2 pyridyl)

 -1H Pyrazole 3-Carbon] — 2 Fluoromethylpyrrolidine

[0790] [Chemical 175]

参考例 4の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (2 ピリジル）—1H ピラゾ 一ルー 3 カルボン酸（297mg)と参考例 54の（2R)— 2 フルォロメチルピロリジン 塩酸塩（140mg)とを用いて、実施例 5と同様の方法で、標題ィ匕合物（240mg, 63% )を固体として得た。

Reference Example 4 1- (6-Methoxy-3 pyridazil) -5- (2 Pyridyl) -1H Pyrazo One-Lou 3 Carboxylic acid (297 mg) and Reference Example 54 (2R) -2 Fluoromethylpyrrolidine Hydrochloride The title compound (240 mg, 63%) was obtained as a solid in the same manner as in Example 5 using the salt (140 mg).

 'H-NMR (400MHz, CDC1) δ: 1.92— 2.08 (4Η, m), 3.71—4.82 (5Η,

 Three

m), 4.12 (3H, s), 7.14 (1H, dd, J = 9.3, 5.9Hz), 7.20— 7.25 (2H, m), 7.59-7.63 (1H, m), 7.73— 7.82 (2H, m), 8.40-8.42 (1H, m). ESI— MSm / z: 383 (M + H) +.

[0792] [Example 88] (2S) — 1— [1— (6—Methyl 3 pyridyl) 5— (1—Methyl IH—pyrrole—3 yl) IH pyrazole—3 carbol] — 2 strength rubermoyl pyrrolidine

[0793] [Chemical 176]

[0794] Reference Example 14 1 (6-Methyl-3-pyridyl) -5- (5-Methyl-1H-Pyrroyl 3-Ill) 1H Pyrazole 3 Carboxylic acid (250 mg) -Prolinamide (12 lmg) The title compound (127 mg, 34%) was obtained as an amorphous product in the same manner as in Example 1.

 'H-NMR (400MHz, CDCl) δ: 1.99— 2.10 (3Η, br), 2.60 (3Η, s), 3.6

 Three

 1 (3H, s), 4.10 (1H, m), 4.86 (1H, d, J = 5.24Hz), 5.38 (1H, br), 5.89

(IH, t, J = 2.08Hz), 6.52 (2H, m), 6.91 (IH, s), 7.21 (IH, d, J = 8.30

Hz), 7.66 (IH, d, J = 5.62Hz), 8.59 (IH, s).

 FAB MSm / z: 379 (M + H) +.

[0795] [Example 89] 1— [5— [1 1 (2 amino) ethyl IH pillow 1 3] 1 1 (6

—Methylviridine— 3—yl) —1H pyrazole—3-carbol] — 4, 4 difluoropiperidine

[0796] [Chemical 177]

[0797] 1) 4,4-Difluoro- 1 [1 6 Methylpyridine 3-yl) 5- (1Η-Pyro (Lu 3—yl) -1H-pyrazole 3 carbo] piperidine Reference Example 58, 3) 1 (6 methylpyridine 3 yl) -5- (1H—pyrrole 3 yl) 1H pyrazole 3 — Using carboxylic acid (0.335 g) and 4,4 difluoropiperidine hydrochloride (0.316 g) of Reference Example 18 in the same manner as in Example 1, 4, 4 difluoro 1 [1— (6-methylpyridine 3 yl) -5- (1H-pyrrole 3 yl) 1H pyrazole-3 carbo] piperidine (0.465 g, quantitative) was obtained as an amorphous substance.

 'H-NMR (400MHz, CDC1) δ: 2.02— 2.15 (4Η, m), 2.63 (3Η, s), 3.9

 Three

 0 (2H, br), 4.19 (2H, br), 6.01—6.05 (1H, m), 6.66— 6.70 (1H, m), 6.72-6.77 (1H, m), 6.83 (1H, s ), 7.22 (1H, d, J = 8.3Hz), 7.65 (1H, dd, J = 2.5, 8.3Hz), 8.42 (1H, br), 8.57 (1H, d, J = 2.5Hz).

EI-MSm / z: 371 (M ⁺ ).

2) 1— [5— (1—Aryl—1H pyrrole—3—yl) —1— (6-Methylpyridine—3—yl) 1H Pyrazole—3 Carboyl] —4,4-Difluoropiperidine

 4, 4-Difluoro 1- [1- (6 Methylpyridine-3 yl) 5-(1H Pyrro 1-Lu 3-yl)-1H Pyrazole-3-Carboyl] piperidine (0.465 g) N , N-dimethylformamide (10 ml) was added with sodium hydride (41. Omg) at 0 ° C and stirred for 10 minutes. To the reaction solution was added allyl iodide (0.171 ml), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution to separate it. Furthermore, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-methanol) to give 1- [5-(1-aryl- 1H pyrrole-3-yl). —1— (6 —Methylviridine-3-yl) —1H Pyrazole-3-carbol] — 4, 4 Difluoropiperidine (0.420 g, 82%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.00— 2.16 (4Η, m), 2.63 (3Η, s), 3.9

 Three

0 (2H, br), 4.19 (2H, br), 4.39—4.45 (2H, m), 5.02— 5.14 (1H, m), 5.18-5.25 (1H, m), 5.86— 5.97 (2H , m), 6.51— 6.58 (2H, m), 6.79 (1H, s), 7.21 (1H, d, J = 8.3Hz), 7.65 (1H, dd, J = 2.4, 8.3Hz), 8.57 ( (1H, d, J = 2.4Hz).

 FAB— MSm / z: 412 (M + H) +.

[0799] 3) 4,4-Difluoro- 1— [5— [1— (2, 3 Dihydroxy) propyl 1H pyrrole — 3 yl] 1— (6 Methylpyridine — 3 yl) 1H Pyrazole — 3 carbol] pi Peridine

 1 [5— (1-aryl 1H-pyrrole 3-yl) 1 (6 methylpyridine 3-yl) -1H pyrazole-3-carbol] — 4, 4 of difluoropiperidine (0.4 20 g) To a mixed solution of tetrahydrofuran (12 ml), methanol (3 ml), and water (4 ml), N-methylmorpholine-N-oxide (0.477 g) and osmium tetroxide (37.5 mg) were added at room temperature and stirred for 1.5 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was stirred for 20 minutes. The reaction solution was extracted with ethyl acetate, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-methanol) to produce 4, 4 difluoro 1- [5-[1- (2, 3 dihydroxy) pro Pyr-1H pyrrole-3-yl] 1- (6-methylpyridine-3-yl) 1H-virazole-3 carbo] piperidine (0.455 g, quantitative) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.00— 2.14 (4Η, br), 2.63 (3Η, s), 3.4

 Three

 3 (1H, dd, J = 5.1, 11.0Hz), 3.61 (1H, dd, J = 3.7, 11.0Hz), 3.83— 3.99 (5H, m), 4.17 (2H, br), 5.95— 6.00 (1H, m), 6.51— 6.57 (1H, m), 6.60-6.65 (1H, m), 6.79 (1H, s), 7.28 (1H, d, J = 8.3Hz), 7.78 (1H, dd, J = 2.5, 8.3 Hz), 8.46 (1H, d, J = 2.5Hz).

 FAB-MSm / z: 446 (M + H) +.

[0800] 4) 4, 4-Difluoro- 1— [5— (1 Formylmethyl- 1H—Pyroluene 3 yl) 1— (6-Methylpyridine— 3-yl) —1H Pyrazole- 3-Carboyl] pipette Lysine Above 4, 4 Difluoro 1— [5— [1— (2, 3 Dihydroxy) propyl 1H Pyro 1 Lu 3 yl] 1— (6-Methylpyridine 3 yl) 1H-Pyrazole 3 Carbol ] To a mixed solution of piperidine (0.455 g) in tetrahydrofuran (5 ml), methanol (5 ml), and water (5 ml), sodium metaperiodate (0.352 g) was added at room temperature for 1.5 hours. Stir. Cold water and ethyl acetate were added to the reaction solution for liquid separation. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and 4,4-difluoro-1 [5— (1 formylmethyl-1 H pyrrole-3-yl) -1- (6-methylpyridine-3-yl) -1H pyrazole-3 -Carbol] piperidine (0.352 g, 83% over 2 steps) was obtained as amorphous.

[0801] 5) 1— [5 -— [1- (2-Benzylamino) ethyl-111-pyrrole-3-yl] -1- (6—methylviridine-3-yl) —1H pyrazole-3-carbol] — 4, 4 Difluoropiperidine

 4, 4 Difluoro- 1— [5— (1-Formylmethyl-1H pyrrole-3-yl) —1— (6-Methylpyridine-3-yl) —1H Pyrazol-3-carbol] piberidine ( To a solution of 0.352 g) in ethanol (10 ml) was added benzylamine (0.465 ml), acetic acid (0.243 ml), and sodium cyanoborohydride (0.165 g) at 0 ° C. Stir for 5 hours. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added and separated. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-methanol). 1- [5-[1- (2-benzylamino) ethyl- 1H pyrrole-3 —Yil] 1— (6-Methylpyridine—3 —yl) — 1H Pyrazole-3-Carboyl] — 4, 4 Difluoropiperidine (0.41 2 g, 96%) was obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 2.00— 2.15 (4Η, m), 2.60 (3Η, s), 2.9

 Three

 0 (2H, t, J = 6.1 Hz), 3.74 (2H, s), 3.86— 3.96 (2H, br), 3.92 (2H, t, J = 6.1 Hz), 4. 19 (2H, br), 5. 90— 5. 96 (1H, m), 6. 51— 6. 57 (1H, m), 6.5-8-6.63 (1H, m), 6. 79 (1H, s), 7. 15 (1H, d, J = 8.3 Hz), 7. 20— 7. 4 0 (5H, m), 7. 61 (1H, dd, J = 2.4, 4 8. 3Hz), 8. 56 (1H, d, J = 2.4Hz). FAB MSm / z: 505 (M + H) +.

[0802] 6) Title compound

1- [5— [1— (2-Benzylaminoethyl) -1H-pyrrole-3-yl] -1— (6-methylpyridine-3-yl) -1H pyrazole-3-carbol] — 4, 4 gifs To a solution of chloropiperidine (0.419g) in methanol (10ml), add 1M ethanolic hydrochloric acid solution (0.831ml) and 20% palladium-carbon (0.310g) at room temperature, and in a hydrogen atmosphere 2 Stir for days. After the catalyst was filtered off, the solid was washed with methanol. To the combined solution of the filtrate and the washing solution, a saturated sodium hydrogen carbonate aqueous solution and a black formaldehyde methanol (10: 1) mixed solution were added for liquid separation. Further, the aqueous layer was extracted with a mixed solution of black mouth form-methanol (10: 1), and the combined organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (black mouth form methanol (including ammonia)) to give the title compound (0.154 g, 45%) as an oil. Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 1.90— 2.15 (4Η, m), 2.62 (3Η, s), 3.0

 Three

 2 (2H, t, J = 5.8Hz), 3.86— 3.96 (4H, m), 4. 19 (2H, br), 5.91— 5.97 (1H, m), 6.56-6.65 (2H, m), 6.80 ( 1H, s), 7.22 (1H, d, J = 8.3Hz), 7.65 (1H, dd, J = 2.5, 8.3Hz), 8.56 (1H, d, J = 2.5Hz).

 FAB— MSm / z: 415 (M + H) +.

[0803] 7) Hydrochloride of the title compound

 Title compound 1 [5— [1 2 aminoethyl) 1 H-pyrrole 3-yl] 1-(6-methylpyridine-3-yl) -1H pyrazole-3-carbol] -4, 4 To a solution of difluoropiperidine (98.4 mg) in chloroform, ethyl ether and hexane was added 1 M hydrochloric acid ethanol (0.237 ml) at room temperature and stirred. The precipitated solid was collected by filtration to give the title compound (88. Omg, 82%).

 'H-NMR (400MHz, DMSO-d) δ: 1.90— 2.05 (4Η, m), 2.49 (3Η, s)

 6

 , 3.02-3.13 (2H, m), 3.27— 3.43 (2H, m), 3.68 (2H, br), 5.76 (1H, br), 6.72 (2H, br), 6.82 (1H, br), 7.38 (1H , d, J = 8.3Hz), 7.75 (1H, dd, J = 2.5, 8.3Hz), 7.86 (3H, br), 8.39 (1H, d, J = 2.5Hz).

ESI-MSm / z: 415 (M + H) ⁺ .

 [0804] [Example 90] 4— [1 (6-methoxypyridazine 3 yl) 5— [1-methyl-1H pyridine 3 yl] 1 H pyrazole 3 carbo] morpholine

[0805] [Chemical 178]

[0806] Reference Example 55-1 (6-methoxypyridazine 1- 3 yl) -5- (1-methyl-1H-pyrrole 1-ru 3-yl) 1H pyrazole 3-carboxylic acid (0.195 g) and morpholine (0.17 g) In the same manner as in Example 5, the title compound (0.152 g, 63%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.62 (3Η, s), 3.67— 3.85 (6Η, m), 4.0

 Three

 9 (2H, br), 4.19 (3H, s), 6.05 (1H, t, J = 2. OHz), 6.52 (1H, t, J = 2. OH z), 6.80 (1H, s), 6.82 (1H, t, J = 2. OHz), 7.07 (1H, d, J = 9.3Hz), 7.5

4 (1H, d, J = 9.3Hz).

 ESI— MSm / z: 369 (M + H) +.

[Example 91] 4-ethylyl 1 [1 (6-methoxypyridine-3-yl) -5 (pyridine)

— 2 yl) 1H pyrazole-3 carbol] — 3 oxopiperazine

[0808] [Chemical 179]

参考例 3の 1— (6—メトキシピリジン— 3—ィル）—5— (ピリジン— 2—ィル）—1H— ピラゾール 3 カルボン酸（0.254g)と参考例 56の 1 ェチル 2 ォキソピペラ ジン塩酸塩 (0.201g)とを用いて、実施例 1と同様の方法で、標題化合物（0.322g , 93%)をアモルファス状物質として得た。

1- (6-Methoxypyridine-3-yl) -5- (pyridine-2-yl) -1H-pyrazole 3 carboxylic acid (0.254 g) of Reference Example 3 and 1-ethyl-2-oxopiperazine hydrochloride of Reference Example 56 The title compound (0.322 g, 93%) was obtained as an amorphous substance in the same manner as in Example 1 using the salt (0.201 g).

'H-NMR (400MHz, CDC1) δ: 1.17 (3Η, t, J = 7.1Hz), 3.44—3.56 (4 H, m), 3.96 (3H, s), 4.03 (1H, br), 4.37—4.45 (2H, m), 4.81 (1H, br

), 6.74-6.80 (1H, m), 7.19— 7.30 (2H, m), 7.38— 7.78 (3H, m), 8.

09 (lHXl / 2, br), 8.14 (lHXl / 2, br), 8.52 (1H, d, J = 4.4Hz).

 ESI-MSm / z: 407 (M + H) +.

[0810] [Example 92] 4- [1 (6-methoxypyridazine-3 yl) -5- (1H-pyrrole-3 yl) 1H pyrazole-3 carbol] morpholine

[0811] [Chemical 180]

[0812] Reference Example 57 1- (6-methoxypyridazine-3-yl) -5- (1H pyrrole-3-yl) 1 1H-pyrazole 1 3-carboxylic acid (0.291 g) and morpholine (0.267 ml) ) To give the title compound (0.343 g, 95%) as a solid in the same manner as in Example 5. 'H-NMR (400MHz, CDC1) δ: 3.67— 3.85 (6Η, m), 4.06—4.12 (2Η,

 Three

 m), 4.18 (3Η, s), 6.16— 6.20 (1H, m), 6.70— 6.75 (1H, m), 6.84 (1H

, s), 7.01-7.06 (1H, m), 7.08 (1H, d, J = 9.3Hz), 7.55 (1H, d, J = 9.3

Hz), 8.40 (1H, br).

 ESI— MSm / z: 355 (M + H) +.

[0813] [Example 93] 4— [5— (1 acetylyl 1H—pyrrole 3-yl) 1 (6-methoxypyridazine-3 yl) 1H pyrazole-3 carbol] morpholine

[0814] [Chemical 181]

[0815] 実施例 92の 4 [1 （6—メトキシピリダジン一 3 ィル）ー5—（1H—ピロ一ルー 3 —ィル）一 1H—ピラゾールー 3—カルボ-ル]モルホリン（0.122g)のジクロロメタン（ 3. Oml)と 1, 4 ジ才キサン（5. Oml)混合溶液に、室温でトリエチノレアミン（0.191 ml),無水酢酸（0.0976ml) ,および 4 （ジメチルァミノ）ピリジン（13.2mg)を添 加し、 70°Cで 19時間攪拌した。空冷後、反応液に水とクロ口ホルムを力卩ぇ分液した。 さらに、水層をクロ口ホルムで抽出し、合わせた有機層を飽和食塩水で洗浄後、無水 硫酸ナトリウムで乾燥した。濾別後、溶媒を減圧下留去し得られた残渣をシリカゲル 薄層クロマトグラフィー（クロ口ホルム一メタノール)で精製し、標題ィ匕合物（90.8mg, 67%)を固体として得た。

[0815] Example 92-4 [1 (6-Methoxypyridazine-1 3 yl) -5- (1H-Pyrrolulu 3 -yl) -1 1H-pyrazole-3-carbol] morpholine (0.122 g) Triethylenamine (0.191 ml), acetic anhydride (0.0976 ml), and 4 (dimethylamino) pyridine (13.2 mg) at room temperature in a mixture of dichloromethane (3 Oml) and 1,4 didioxane (5. Oml) Was added and stirred at 70 ° C for 19 hours. After air cooling, water and black mouth form were vigorously separated into the reaction solution. Further, the aqueous layer was extracted with chloroform, and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (black mouth form-methanol) to obtain the title compound (90.8 mg, 67%) as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.53 (3Η, s), 3.57—3.74 (6Η, m)

 6

 , 3.90-3.98 (2H, m), 4.09 (3H, s), 6.17— 6.22 (1H, m), 7.04 (1H, s

), 7.41-7.44 (1H, m), 7.51 (1H, d, J = 9.3Hz), 7.58—7.62 (1H, m),

7.97 (1H, d, J = 9.3Hz).

ESI-MSm / z: 397 (M + H) ⁺ .

[0816] [Example 94] 4-Methyl-1- [1— (6 Methylpyridine-3-yl) -5- (1H-Pyro-one-roux-three-yl) 1H Pyrazole-3 Carboyl] — 3-oxopiperazine

[0817] [Chemical 182]

参考例 58の 3)の 1 （6 メチルピリジンー3 ィル）ー5—（1H—ピロ一ルー 3— ィル） 1H ピラゾールー 3—力ルボン酸（0.235g)と参考例 46の 1ーメチルビペラ ジン— 2—オン (0.299g)とを用いて、実施例 1と同様の方法で、標題化合物（0.16 7g, 52%)をアモルファス状物質として得た。

Reference Example 58-3) 1 (6 Methylpyridine-3-yl) -5- (1H-Pyrroyl 3-yl) 1H Pyrazole-3-Strong Rubonic Acid (0.235 g) and Reference Example 46 1-Methylbiperazine-2 The title compound (0.16 7 g, 52%) was obtained as an amorphous substance in the same manner as in Example 1 using —one (0.299 g).

'H-NMR (400MHz, CDC1) δ: 2.61 (3Η, s), 3.01 (3Η, s), 3.40—3.52 (2H + 1 / 2X1H, m), 4.02 (1H, br), 4.40 (1H + 1 / 2X IH, m), 4.81 (1 H, br), 5.94 (1H, br), 6.60— 6.72 (2H, m), 6.76— 6.87 (1H, m), 7.2 2 (1H, d, J = 8.3Hz), 7.58— 7.70 (1H, m), 8.53 (1 / 2X1H, br), 8.58 (1/2 X1H, br), 9.73 (1H, br).

 ESI— MSm / z: 365 (M + H) +.

 [0819] [Example 95] 4-Methoxy 1 [1- (6 Methylpyridine 3-yl) 5- (1H-Pyrrol 3-yl) -1H-pyrazole 3 carbo] piperidine

 [0820] [Chemical 183]

[0821] Reference Example 58, 3) 1 (6 Methylpyridine-3-yl) -5- (1H-Pyrroyl 3-yl) -1H Pyrazole-3-carboxylic acid (0.245 g) and Reference Example 23 4— The title compound (0.205 g, 61%) was obtained as an amorphous substance in the same manner as in Example 1 using methoxypiperidine hydrochloride (0.204 g).

 'H-NMR (400MHz, CDCl) δ: 1.66 (2Η, br), 1.93 (2Η, br), 2.60 (3H

 Three

 , s), 3.37 (3H, s), 3.50 (2H, br), 3.72 (1H, br), 4.08 (IH, br), 4.27 (1 H, br), 5.95 (1H, br), 6.60— 6.74 (3H, m), 7.19 (1H, d, J = 8. OHz), 7.63 (IH, dd, J = 2.7, 8. OHz), 8.56 (IH, d, J = 2.7Hz), 9.46 (IH, br). ESI— MSm / z: 366 (M + H) +.

 [0822] [Example 96] 1— [5 -— (1-ethylyl IH pyro-l-yl 3 yl) 1 1 (6-methylpyridine-3-yl) —1H pyrazole- 3-carbol] —4-methyl- 3-Oxopipe Razine

[0823] [Chemical 184]

[0824] Reference Example 58 5- (1-ethylyl 1H-pyrrole 3-yl) -1 (6 methylpyridin-3-yl) -1H pyrazole-3-carboxylic acid (0.120 g) and Reference Example 22 The title compound (0.120 g, 75%) was obtained as an amorphous substance in the same manner as in Example 5 using 1-methylbiperazine-2-onetrifluoroacetate (0.131 g).

 'H-NMR (400MHz, CDC1) δ: 1.38 (3Η, t, J = 7.4Hz), 2.63 (3H, s), 3

 Three

 .01 (3H, s), 3.40-3.55 (2H + 1HX 1/3, m), 3.86 (2H, q, J = 7.4Hz), 4.02 (IH, br), 4.42 (lH + lHX2 / 3, m ), 4.81 (IH, br), 5.88 (IH, br), 6.52-6.62 (2H, m), 6.81 (lHX2 / 3, br), 6.86 (lHXl / 3, br), 7.20 -7.30 (1H, m ), 7.61-7.74 (IH, m), 8.55 (lHX2 / 3, br), 8.60 (1H Xl / 3, br).

 ESI— MSm / z: 393 (M + H) +.

[0825] [Example 97] 4- [1- (6-Methoxypyridine-3-yl) -5- (1-methyl-1H-imidazole-4 yl) 1H pyrazole-3 carbo] morpholine

[0826] [Chemical 185]

参考例 34の 1— (6—メトキシピリジン— 3—ィル）—5— (1—メチル 1H—イミダゾ ール 4 ィル） 1H ピラゾール 3 カルボン酸 (102mg)とモルホリン（45 1) とを用いて、実施例 5と同様の方法で、標題ィ匕合物（99mg, 79%)を固体として得た Ή-NMR (400MHz, CDC1 ) δ :3.66 (3H, s), 3.72— 3.79 (6H, m), 3.9

Using Reference Example 34 1- (6-Methoxypyridine-3-yl) -5- (1-methyl 1H-imidazole 4 yl) 1H Pyrazole 3 Carboxylic acid (102 mg) and Morpholine (45 1) In the same manner as in Example 5, the title compound (99 mg, 79%) was obtained as a solid. NMR-NMR (400MHz, CDC1) δ: 3.66 (3H, s), 3.72—3.79 (6H, m), 3.9

 Three

 8 (3H, s), 4.10 (2H, s), 6.68 (1H, s), 6.80 (1H, d, J = 8.8Hz), 7.00 (1 H, s), 7.42 (1H, s), 7.68 (1H, dd, J = 8.8, 2.7Hz), 8.23 (1H, d, J = 2.7Hz).

 ESI— MSm / z: 369 (M + H) +.

[0828] [Example 98] 1— [5 -— (5-Aminomethylviridine-2-yl) —1-— (6-methylpyridine)

—3—yl) —1H pyrazole—3-carbol] — 4, 4 difluoropiperidine [0829] [Chemical Formula 186]

[0830] In the autoclave, 1- [5- (5 Cyanpyridine-2-yl) 1- (6-methylpyridine-3-yl) 1H pyrazole-3 carbol] -4, 4-difluoropiperidine (Example 4) 1. 12 g) and nickel on silica Zanoremina (˜65%, 200 mg) were suspended in a 2M ammonia ethanol solution (40 ml), and the mixture was heated and stirred at 120 ° C. for 1 hour in a hydrogen atmosphere (8 atm). After cooling with air and filtering through celite, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (a lower layer solvent of chloroform-form methanol-water) to give the title compound (0.62 g, 55%) was obtained as an oil.

ESI-MSm / z: 413 (M + H) ⁺ .

 [0831] [Example 99] 1 [5- (5 Hydroxymethylpyridine 2-yl) 1 (6 Methylpyridin-3-yl) -1H Pyrazole 3-Carbonyl] — 4, 4 Difluoropiperidine

[0832] [Chemical 187]

[983] Example 98 1- [5- (5-Aminomethylpyridine-2-yl) -1- (6-methylpyridin-3-yl) -1H-pyrazole-3-carbol] -4 , 4-Difluoropiperidine (0.62 g) in water (20 ml) and acetic acid (5 ml) mixed solution was added sodium nitrite (519 mg) at room temperature and stirred for 1.5 hours. The reaction solution was made alkaline by adding a saturated aqueous solution of sodium bicarbonate under ice-cooling, and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform form-methanol) to obtain the title compound (131 mg, 21%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.09 (4Η, br s), 2.60 (3H, s), 3.92 (2H

 Three

 , s), 4.19 (2H, s), 4.74 (2H, s), 7.14 (1H, s), 7.21 (1H, d, J = 8.3Hz),

7.44 (1H, d, J = 8.1Hz), 7.62 (1H, dd, J = 8.3, 2.4Hz), 7.76 (1H, d, J

= 8. 1Hz), 8.38 (1H, d, J = 2.4Hz), 8.47 (1H, s).

 ESI— MSm / z: 414 (M + H) +.

[0834] [Example 100] 4- [5- (5-Cyanopyridine-2-yl) -1- (6-methoxypyridazine]

 -3—yl) -1H-pyrazole—3-carbol] morpholine

[0835] [Chemicalization 188]

[0836] 参考例 59の 5— (5 シァノピリジン一 2—ィル） 1— (6—メトキシピリダジン一 3— ィル） 1H ピラゾール 3 カルボン酸（ 179mg)とモルホリン（73 1)とを用いて 、実施例 5と同様の方法で、標題ィ匕合物（186mg, 86%)を固体として得た。

[0836] Reference Example 59 5- (5 Cyanopyridine-2-yl) 1- (6-Methoxypyridazine-1-3-yl) 1H Pyrazole 3 Using carboxylic acid (179 mg) and morpholine (73 1) In the same manner as in Example 5, the title compound (186 mg, 86%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.72— 3.83 (6Η, m), 4.12 (5Η, s), 7.1

 Three

 9 (1H, d, J = 9.3Hz), 7.24 (1H, s), 7.71 (1H, d, J = 4.2Hz), 7.83 (1H, d, J = 9.3Hz), 8.02 (1H, dd, J = 8.2, 2.1Hz), 8.66 (1H, d, J = l.2Hz).

ESI-MSm / z: 392 (M + H) ⁺ .

[0837] [Example 101] 4— [5— (5 aminomethylviridine-2-yl) 1— (6-methoxypyridazine-3 yl) 1H pyrazole 3 carbo] morpholine

[0838] [Chemical 189]

[0839] Example 100 4- [5- (5 Cyanopyridin-2-yl) -1- (6-methoxypyridazine-3-yl) -1H pyrazole-3-carbol] morpholine (182 mg) and nickel The title compound (162 mg, 88%) was obtained as an oil in the same manner as in Example 98 using on silica Z alumina (˜65%, lOOmg).

 ESI— MSm / z: 396 (M + H) +.

 [0840] [Example 102] 4- [5 -— (5-Hydroxymethylpyridine 2-yl) 1 (6-methoxypyridazine-3 yl) 1H pyrazole-3 carbol] morpholine

[0841] [Chemical 190]

[0842] Example 101 4- [5- (5 Aminomethylviridine-2-yl) -1- (6-methoxypyridazine 3-yl) -1H-pyrazole 3-carbonyl] morpholine (16 lmg) and nitrite The title compound (97 mg, 60%) was obtained as an amorphous substance in the same manner as in Example 99 using sodium acid (84 mg).

ESI-MSm / z: 397 (M + H) ⁺ .

 [0843] [Example 103] 4- [5- (5 Fluoromethylpyridine-2-yl) -1 (6-methoxypyridazine 3 yl) 1H pyrazole 3 carbo] morpholine

 [0844] [Chemical 191]

[0845] Example 102 4- [5- (5 Hydroxymethylpyridine-2-yl) -1- (6-methoxypyridazine-3yl) 1H pyrazole-3 carbo] morpholine (96 mg) in dichloro To a methane (10 ml) solution, bis (2-methoxyethyl) amino sulfur trifluoride (53 μ 1) was added with cooling at −15 ° C., and the mixture was stirred for 20 minutes. To the reaction solution, a saturated aqueous solution of sodium hydrogen carbonate was made alkaline and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chromoform formmethanol) to give the title compound (25 mg, 24%) as a solid. NMR-NMR (400MHz, CDCl) δ: 3.73— 3.85 (6H, m), 4.12 (5H, s), 5.4

 Three

 1 (2H, d, J = 47.4Hz), 7.15 (1H, d, J = 9.0Hz), 7.16 (1H, s), 7.63 (1H

, d, J = 8.1Hz), 7.76-7.80 (2H, m), 8.41 (1H, s).

 ESI— MSm / z: 399 (M + H) +.

[0846] [Example 104] 1— [5— (1-Methyl-1H imidazole-4-yl) 1 1 (6-Methylviridine-3-yl) —1H Pyrazole-3-Carboyl] — 4, 4 Difluoropiperidine

[0847] [Chemical 192]

[0848] Reference Example 60 5- (1-Methyl-1H-imidazole-4-yl) 1 (6 Methylpyridine-3-yl) -1H Pyrazole-3-carboxylic acid (lOOmg) and Reference Example 18, 4, 4-difluo The title compound (115 mg, 84%) was obtained as a solid in the same manner as in Example 5 using lopiperidine hydrochloride (67 mg).

 'H-NMR (400MHz, CDCl) δ: 2.06 (4Η, brs), 2.62 (3Η, s), 3.67 (3H,

 Three

 s), 3.91 (2H, s), 4.16 (2H, s), 6.78 (1H, d, J = l.2Hz), 6.98 (1H, s),

7.24 (1H, d, J = 8. OHz), 7.40 (1H, d, J = l.0 Hz), 7.73 (1H, dd, J = 8.

2, 2.6Hz), 8.54 (1H, d, J = 2.7Hz).

ESI-MSm / z: 387 (M + H) ⁺ .

[0849] [Example 105] (+) (3S) —4— [1— (6-Methoxypyridazine-3 yl) -5- (2 pyridyl) 1H pyrazole-3 carbol] 3 methylmorpholine

[0850] [Chemical 193]

[0851] 1) (5S) 5-Methyl-3 morpholinone

 To a solution of (2S) -2-amino-1-propanol (0.665 ml) in tetrahydrofuran (100 ml) was added sodium hydride (55%, 0.409 g) at room temperature and stirred for 35 minutes. To the reaction solution, ethyl acetate (0.900 ml) was stirred for 30 minutes and then heated to reflux for 3 hours. After air-cooling, the reaction solution is filtered, and the filtrate solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (ethyl acetate n-xane) to give a crude product of (5S) 5-methyl-3-morpholinone. (0.170 g, 17%) was obtained as an amorphous substance.

 [0852] 2) (3S) 3 Methylmorpholine

 Lithium aluminum hydride (0.121 g) was added to a solution of the above (5S) -5-methyl 3 morpholinone crude product (0.170 g) in tetrahydrofuran (20 ml), and the mixture was heated to reflux for 19 hours. After air cooling, anhydrous magnesium sulfate and methanol were added to the reaction solution, and the reaction solution was filtered. A 1M hydrochloric acid ethanol solution (5 ml) was added to the filtrate. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product of (3S) -3-methylmorpholine.

 [0853] 3) Title compound

 Using the above (3S) -3 methylmorpholine crude product and 1 (6-methoxy-3-pyridazil) -5- (2 pyridyl) -1H pyrazole-3-carboxylic acid (0.232 g) of Reference Example 4 In the same manner as in Example 1, the title compound (118 mg, 21%) was obtained as a solid.

'H-NMR (400MHz, DMSO-d) δ: 1.31 (3Η, brs), 3.14— 3.30 (1Η, m

 6

), 3.36-3.45 (1 mm, m), 3.55-3.59 (1 mm, m), 3.67 (1 mm, brs), 3.81-3.94 (1 mm, m), 4.03 (3 mm, s), 4.19-4.40 (1H , m), 4.62 (1H, brs), 7.26 (1H, s), 7.34 (1H, ddd, J = 7.6, 4.9, 1.0Hz), 7.47 (1H, d, J = 9.3Hz), 7.77-7.79 (1H, m), 7.89 (1H, ddd, J = 7.8, 7.6, 1.7Hz), 7.98 (1H, d, J = 9.3Hz), 8.36-8.38 (IH, m).

ESI-MSm / z: 381 (M + H) ⁺ .

 [a] 25 + 51.5 ° (cl.01, CHC1).

 D 3

 [Example 106] (—) (2S) — 1 [1— (6-Methoxypyridazine—3 yl) -5- (2 Pyridyl) —1H Pyrazole—3-Carbol] — 2-Methoxy Methylpyrrolidine

[0855] [Chemical 194]

[0856] Reference Example 4 1- (6-Methoxy-1-pyridazil) 5-- (2 Pyridyl) 1H Pyrazo One-Lou 3-Strong Rubonic Acid (0.232 g) and (2S) -2- (Methoxymethyl) pyrrolidine (0.115 ml) was used in the same manner as in Example 1 to obtain the title compound (247 mg, 80%) as a solid.

 'H-NMR (400MHz, CDCl) δ: 1.87— 2.13 (4Η, m), 3.28 (IH, s), 3.3

 Three

 0-3.33 (2 / 3H, m), 3.39 (2H, s), 3.54 (2 / 3H, dd, J = 9.3, 7.1Hz), 3.63 (1 / 3H, dd, J = 9.0, 3.4Hz ), 3.69— 3.76 (4 / 3H, m), 4.00—4.04 (IH, m), 4.10 (1H, s), 4.11 (2H, s), 4.50—4.55 (2 / 3H, m), 5.05— 5 10 (1 / 3H, m), 7.13 (1H, d, J = 9.3Hz), 7.20— 7.25 (2H, m), 7.59— 7.64 (1H, m), 7.73— 7.89 (2H, m), 8.39 — 8.43 (1H, m).

 ESI— MSm / z: 395 (M + H) +.

[a] ²⁵ -83. In (cO.98, CHC1).

 D 3

 [0857] [Example 107] (-) (3R) — 4— [1— (6-Methoxypyridazine 1-yl) 5— (2 Pyridyl) 1H Pyrazole-3 Carbon] 3 Methylmorpholine

[0858] [Chemical 195]

[0859] 1) (5R) -5-Methyl 3 morpholinone

 To a solution of (2R) -2 amino-1-propanol (1.33 ml) in tetrahydrofuran (200 ml), sodium hydride (55%, 0.820 g) was added at room temperature and stirred for 35 minutes. To the reaction solution, black ethyl acetate (1.80 ml) was added at room temperature over 5 minutes, stirred for 25 minutes and then heated to reflux for 17.5 hours. After air cooling, the reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane), and (5R) -5-methyl 3 morpholinone The crude product (0.520 g, 26%) was obtained as an oil.

 2) (3R) 3 Methylmorpholine

 Lithium aluminum hydride (0.342 g) was added to a solution of the crude product (0.520 g) of the above (5R) -5-methyl 3morpholinone (0.520 g) in tetrahydrofuran (60 ml), and the mixture was heated to reflux for 15.5 hours. Magnesium sulfate heptahydrate was added to the reaction solution, and the reaction solution was filtered. A 1M hydrochloric acid ethanol solution (15 ml) was added to the filtrate, and then the solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product of (3R) -3-methylmorpholine.

[0860] 3) Title compound

 Crude product of (3R) -3-methylmorpholine and 1- (6-Methoxy-1-pyridazil) -5- (2-pyridyl) -1H pyrazole-3-carboxylic acid (0.464g) Using and, the title compound (145 mg, 8.4%) was obtained as a solid in the same manner as in Example 1.

 — NMR (CDC1) δ: 1.43 (3 / 2H, brs), 1.45 (3 / 2H, brs), 3.26— 3.7

 Three

8 (4H, m), 3.86-4.02 (1H, m), 4.11 (3H, s), 4.84 (1H, brs), 7.11 (1 H, s), 7.13 (1H, d, J = 9.3Hz ), 7.21-7.24 (1H, m), 7.57-7.60 (1H, m), 7.73-7.79 (2H, m), 8.40-8.42 (1H, m). ESI-MSm / z: 381 (M + H).

 [a] 25-41.3 ° (cl.00, CHC1).

 D 3

 [0861] [Example 108] 4- [1- (6-Methoxy-3-pyridyl) 5- (6-Methyl-3-pyridyl)

)-1H pyrazole-3-carbol] morpholine

[0862] [Chemical 196]

[0863] Using Reference Example 65 1- (6-Methoxy-3 pyridyl) -5- (6-methinole 3 pyridinole) 1 H pyrazole mono 3-carboxylic acid (0.250 g) and morpholine (0.105 ml) In the same manner as in Example 5, the title compound (0.217 g, 71%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.58 (3Η, s), 3.75-3.83 (6Η, m), 3.9

 Three

 6 (3H, s), 4.18 (2H, m), 6.77 (1H, d, J = 8.8Hz), 7.01 (1H, s), 7.16 (1

H, d, J = 8.1Hz), 7.41-7.44 (1H, m), 7.49—7.52 (1H, m), 8.10 (1H

, d, J = 2.7Hz), 8.42 (1H, d, J = 2.4Hz).

 EI-MSm / z: 379 (M +).

[0864] [Example 109] 4— [5— (6 Amino-3 pyridyl) 1— (6-Methoxy-1-pyridyl)

 -1H pyrazole-3-carbol] morpholine

[0865] [Chemical 197]

[0866] 1)4— [5— (6— tert—ブトキシカルボ-ルァミノ— 3 ピリジル）—1— (6—メトキシ — 3 ピリジル） 1H ピラゾール 3 カルボ-ル]モルホリン

[0866] 1) 4— [5— (6— tert-Butoxycarbolamino-3 pyridyl) —1— (6-methoxy-3 pyridyl) 1H pyrazole 3 carbo] morpholine

 Reference Example 66, 5- (6-tert-butoxycarbo-lamino-3-pyridyl) -1- (6-methoxy-3-pyridyl) 1H pyrazole-1-carboxylic acid (0.420 g) and morpholine (0.133 ml) In the same manner as in Example 1, 4 [5- (6-tert-butoxycarbo-lamino-1-pyridyl) 1- (6-methoxy-1-3-pyridyl) 1H pyrazole-1 3 carbol] morpholine ( 0.442 g, 90%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.53 (9Η, s), 3.75― 3.83 (6Η, m), 3.9

 Three

 6 (3H, s), 4.18 (2H, m), 6.76— 6.78 (1H, m), 6.97 (1H, s), 7.44— 7.52 (2H, m), 7.73 (1H, s), 7.95 (1H, d, J = 8.8Hz), 8.11—8.12 (1H, m), 8.19-8.20 (1H, m).

EI-MSm / z: 480 (M ⁺ ).

[0867] 2) Title compound

 4- [5- (6-tert-butoxycarbo-lamino-3-pyridyl) -1] (6-methoxy-3-pyridyl) -1H pyrazole-3-carbol] morpholine (0.434g) in dichloromethane (8.7ml) ) To the solution was added trifluoroacetic acid (4.4 ml) at room temperature and stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and black mouth form were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (black mouth form-methanol) to obtain the title compound (0.225 g, 65%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.75— 3.83 (6Η, m), 3.96 (3Η, s), 4.1

 Three

 7 (2H, m), 4.72 (2H, br), 6.45— 6.48 (1H, m), 6.77 (1H, d, J = 8.8Hz)

, 6.90 (1H, s), 7.24-7.27 (1H, m), 7.51-7.54 (1H, m), 7.99 (1H, m), 8.14 (1H, d, J = 2.7Hz).

EI-MSm / z: 380 (M ⁺ ).

[0868] [Example 110] 1— [1— (6-Methoxy-3 pyridazil) -5- (6-methyl-3 pyridyl) 1H pyrazole 3 carbonyl] 4, 4 difluoropiperidine

[0869] [Chemical 198]

[0870] Reference Example 67 1- (6-Methoxy-3 pyridazil) -5- (6-Methyl-3 pyridyl) — 1H Pyrazole-3-carboxylic acid (0.250 g) and Reference Example 18, 4, 4 difluoro The title compound (0.276 g, 83%) was obtained as a solid in the same manner as in Example 1 using peridine hydrochloride (0.152 g).

 'H-NMR (400MHz, CDC1) δ: 2.08— 2.13 (4Η, m), 2.60 (3Η, s), 3.9

 Three

 3-3.96 (2H, m), 4.13 (3H, s), 4.15—4.16 (2H, m), 6.97 (1H, s), 7.

16 (1H, d, J = 9.3Hz), 7.21 (1H, d, J = 8.1Hz), 7.63— 7.65 (1H, m), 7

.79 (1H, d, J = 9.3Hz), 8.42 (1H, d, J = 2.2Hz).

EI-MSm / z: 414 (M ⁺ ).

[0871] [Example 111] 1— [5— (6 amino-3 pyridyl) 1— (6-methoxy-1-pyridazi

-L) —1H pyrazole- 3-carbol] — 4, 4 difluoropiperidine

[0872] [Chemical 199]

1) 1— [5— (6— tert-Ptoxycarpaminomino 1-pyridyl) 1— (6-methoxy — 3-pyridazil) 1H pyrazole 3 carbonyl] 4, 4 difluoropiperidine

Reference Example 68, 5— (6— tert-butoxycarbo-lamino—3-pyridyl) —1— (6- Toxi-3-pyridazil)-1H Pyrazole-3-carboxylic acid (0.330 g) and 4, 4 difluoropiperidine hydrochloride (0.151 g) in Reference Example 18 were used in the same manner as in Example 1. 1— [5— (6— tert-butoxycarbo-lamino 3-pyridyl) -1— (6-methoxy-3-pyridazil) 1H pyrazole 3 carbonyl] 4, 4 difluoropiperidine (0.421 g, quantitative) Was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.53 (9Η, s), 2.07— 2.11 (4Η, m), 3.9

 Three

 3 (2H, m), 4.13 (3H, s), 4.15 (2H, m), 6.94 (1H, s), 7.13 (1H, d, J = 9.3Hz), 7.62-7.65 (1H, m), 7.73— 7.76 (2H, m), 7.98 (1H, d, J = 8.8 Hz), 8.25 (1H, d, J = 2.0 Hz).

EI-MSm / z: 515 (M ⁺ ).

[0874] 2) Title compound

 Above {1— [5— (6— tert-butoxycarbo-lamino 3-pyridyl) -1— (6-methoxy-3-pyridazil) 1H pyrazole 3 carbo] 4, 4 difluoropiperidine (0.411 g ) To give the title compound (0.265 g, 80%) as a solid in the same manner as in Example 109, 2).

 'H-NMR (400MHz, CDC1) δ: 2.06— 2.11 (4Η, m), 3.92 (2Η, m), 4.

 Three

 14 (3H, s), 4.14 (2H, m), 4.78 (2H, br), 6.50— 6.52 (1H, m), 6.88 (1

H, s), 7.12 (1H, d, J = 9.3Hz), 7.47— 7.50 (1H, m), 7.70 (1H, d, J = 9

.3Hz), 8.01 (1H, m).

 EI-MSm / z: 415 (M +).

[Example 112] 4- [5- (1H-imidazole-4-yl) -1- (6-methoxy-3-pyridyl) 1H pyrazole-3 carbo] morpholine

[0876] [Chemical 200]

[0877] 参考例 69の 5—（1H—イミダゾールー 4ーィル）ー1 （6—メトキシー3 ピリジル） — 1H ピラゾール一 3—カルボン酸（0.220g)とモルホリン（0. 134ml)とを用いて 、実施例 1と同様の方法で、標題化合物（0.112g, 40%)を固体として得た。

[0877] Reference Example 69 5- (1H-imidazole-4-yl) -1 (6-methoxy-3-pyridyl) — 1H Pyrazole 1-carboxylic acid (0.220 g) and morpholine (0.134 ml) were used. In the same manner as in Example 1, the title compound (0.112 g, 40%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.80 (6Η, m), 3.97 (3Η, m), 4.

 Three

 10 (2H, m), 6.78-6.80 (2H, m), 7.02 (1H, s), 7.61— 7.64 (1H, m), 7

.66 (1H, s), 8.21 (1H, d, J = 2.9Hz).

EI-MSm / z: 354 (M ⁺ ).

[0878] [Example 113] 1— [5— (1H-imidazole-4-yl) -1-1- (6-methoxy-3-pyridyl) 1H pyrazole 3 carbonyl] 4,4 difluoropiperidine

[0879] [Chem 201]

[0880] Reference Example 69 5- (1H-imidazole-4-yl) -1 (6-methoxy-3-pyridyl) — 1H pyrazole-3-carboxylic acid (0.220 g) and Reference Example 18, 4, 4 difluoropiperidine hydrochloride (0.243) In the same manner as in Example 1, the title compound (0.195 g, 62%) was obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 2.00— 2.09 (4Η, m), 3.76 (2Η, m)

 6

 , 3.91 (3H, s), 4.06 (2H, m), 6.92— 6.95 (2H, m), 7.06 (1H, br), 7.7

0 (1H, s), 7.80-7.84 (1H, m), 8.28 (1H, d, J = 2.7Hz).

 EI— MSmZz: 388 (M +).

[0881] [Example 114] 4— [1— (6-Methoxy-3-pyridyl) -5- (1H pyrazole-4-yl) 1H-pyrazole-3 carbo] morpholine

[0882] [Chemical 202]

[0883] Reference Example 70 1- (6-Methoxy-1-pyridyl) 5-- (1H Pyrazole 1-4-yl) — Using 1H Pyrazole 1-3-carboxylic acid (0.250 g) and morpholine (0.153 ml) Then, the title compound (0. llOg, 34%) was obtained as a solid in the same manner as in Example 1.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.82 (6Η, m), 3.99 (3Η, s), 4.1

 Three

 4—4.17 (2H, m), 6.82 (1H, d, J = 8.8Hz), 6.93 (1H, s), 7.46 (2H, br)

, 7.57 (1H, dd, J = 8.8, 2.7Hz), 8.20 (1H, d, J = 2.7Hz).

EI-MSm / z: 354 (M ⁺ ).

[0884] [Example 115] 4— [1 (6 methoxy 3 pyridyl) 5— (1 methyl 1H pyrazole 4 yl) -1H-pyrazole 3 carbo] morpholine

[0885] [Chemical 203]

参考例 61の 1— (6—メトキシ一 3 ピリジル） 5— (1—メチル 1H ピラゾール —4—ィル） 1H ピラゾール一 3—カルボン酸（1.00g)とモルホリン（0.349ml) とを用いて、実施例 5と同様の方法で、標題化合物（1. 13g, 91%)を固体として得 た。

Using Reference Example 61 1- (6-Methoxy-1-pyridyl) 5- (1-methyl 1H pyrazole-4-yl) 1H pyrazole 1-3-carboxylic acid (1.00 g) and morpholine (0.349 ml), In the same manner as in Example 5, the title compound (1.13 g, 91%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.72— 3.81 (6Η, m), 3.87 (3Η, s), 3.9

 Three

9 (3H, s), 4.15 (2H, m), 6.82 (1H, d, J = 8.8Hz), 6.86 (1H, m), 7.21 ( 1H, s), 7.27-7.28 (1H, m), 7.56—7.59 (1H, m), 8.21 (1H, d, J = 2.7 Hz).

 EI— MSmZz: 368 (M +).

[0887] [Example 116] 4— [1— (6-Methoxy-3-pyridyl) -5- (thiazole-5-yl)

1H-pyrazole—3-carbol] morpholine

[0888] [Chemical 204]

[0889] Using Reference Example 62 1- (6-Methoxy-3-pyridyl) -5- (thiazole-5-yl)-1H-pyrazole-3-carboxylic acid (0.594 g) and morpholine (0.257 ml) In the same manner as in Example 1, the title compound (0.572 g, 78%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.82 (6Η, m), 3.99 (3Η, s), 4.1

 Three

 4 (2H, m), 6.83 (1H, dd, J = 8.8, 0.5Hz), 7.09 (1H, s), 7.55 (1H, dd, J

= 8.8, 2.7Hz), 7.78 (1H, d, J = 0.5Hz), 8.17— 8.18 (1H, m), 8.79 (1

(H, d, J = 0.5Hz).

EI-MSm / z: 371 (M ⁺ ).

[0890] [Example 117] 4— [1— (6-Methoxy-3-pyridyl) -5- (thiazole-2-yl)

1H-pyrazole—3-carbol] morpholine

[0891] [Chemical 205]

[0892] 参考例 63の 1— (6—メトキシ一 3 ピリジル） 5— (チアゾール 2—ィル） 1H —ピラゾールー 3—カルボン酸（0.610g)とモルホリン（0.264ml)とを用いて、実施 例 5と同様の方法で、標題ィ匕合物（0.515g, 69%)を固体として得た。

[0892] Example 63 of Example 63 using 1- (6-methoxy-1-pyridyl) 5- (thiazole 2-yl) 1H-pyrazole-3-carboxylic acid (0.610 g) and morpholine (0.264 ml) In the same manner as in 5, the title compound (0.515 g, 69%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.82 (6Η, m), 4.00 (3Η, s), 4.1

 Three

 3 (2H, m), 6.83 (1H, dd, J = 8.8, 0.5Hz), 7.31 (1H, s), 7.38 (1H, d, J

= 3.2Hz), 7.67 (1H, dd, J = 8.8, 2.7Hz), 7.80 (1H, d, J = 3.2Hz), 8.2

5-8.26 (1H, m).

EI-MSm / z: 371 (M ⁺ ).

[0893] [Example 118] 4— [1— (6-Methoxy-3 pyridyl) -5- (thiazole-4-yl)

1H-pyrazole 3 carbo] morpholine

[0894] [Chemical 206]

[0895] 1- (6-Methoxy-3-pyridyl) 5- (thiazole 4-yl) 1H-pyrazole-3-carboxylic acid (0.244 g) and morpholine (0.105 ml) in Reference Example 64 In the same manner as in Example 5, the title compound (0.140 g, 47%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.82 (6Η, m), 3.98 (3Η, s), 4.1

 Three

 4 (2H, m), 6.81 (1H, d, J = 8.8Hz), 7.17 (1H, s), 7.26 (1H, d, J = 2. OH z), 7.62 (1H, dd, J = 8.8, 2.7Hz), 8.17 (1H, d, J = 2.7Hz), 8.79 (1H, d

, J = 2. OHz).

EI-MSm / z: 371 (M ⁺ ).

[Example 119] 1— [1— (6 Methoxy 3 pyridyl) 5 — (1 Methyl 1H Pyrazo 1-lu 4-yl) — 1H Pyrazole- 3-carbol] — 4-Methoxypiperidine

[0897] [Chemical 207]

[0898] 1- (6-Methoxy-1-pyridyl) of Reference Example 61 5- (1-Methyl 1H pyrazole-4-yl) 1H Pyrazole-3-carboxylic acid (0.200 g) and 4-methoxypiperidine hydrochloride of Reference Example 23 The title compound (0.199 g, 75%) was obtained as a solid in the same manner as in Example 5 using the salt (0.203 g).

 'H-NMR (400MHz, CDC1) δ: 1.66— 1.93 (4Η, m), 3.38 (3Η, s), 3.4

 Three

 6-3.52 (2H, m), 3.73 (1H, m), 3.87 (3H, s), 3.99 (3H, s), 4.09 (1H, m), 4.29 (1H, m), 6.80— 6.82 (2H, m), 7.21 (1H, s), 7.28 (1H, s), 7.

59 (1H, dd, J = 8.8, 2.7Hz), 8.22 (1H, d, J = 2.7Hz).

 EI— MSmZz: 396 (M +).

[0899] [Example 120] 1— [1— (6 Methoxy 3 pyridyl) 5 — (1 Methyl 1H pyrazo 1-lu 4-yl) — 1H Pyrazole 3-carbol] — 4-Methylpiperazine

[0900] [Chemical 208]

参考例 61の 1— (6—メトキシ一 3 ピリジル） 5— (1—メチル 1H ピラゾール —4—ィル） 1H—ピラゾールー 3—カルボン酸（0.200g)と N—メチルビペラジン ( 0. 148ml)とを用いて、実施例 5と同様の方法で、標題化合物（0.112g, 44%)を 固体として得た。

Reference Example 61 1- (6-Methoxy-3-pyridyl) 5- (1-Methyl 1H pyrazole-4-yl) 1H-pyrazole-3-carboxylic acid (0.200 g) and N-methylbiperazine (0.148 ml) Was used to give the title compound (0.112 g, 44%) as a solid in the same manner as in Example 5.

'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 2.52 (4Η, m), 3.84—3.8 7 (2H, m), 3.87 (3H, s), 3.99 (3H, s), 4.14 (2H, m), 6.81 (IH, dd, J =

8.8, 0.7Hz), 6.84 (1H, s), 7.20 (1H, s), 7.28 (IH, d, J = 0.7Hz), 7.5

8 (1H, dd, J = 8.8, 2.7Hz), 8.21-8.22 (1H, m).

EI-MSm / z: 381 (M ⁺ ).

[0902] [Example 121] 1— [1— (6 Methoxy 3 pyridyl) 5 — (1 Methyl 1H Pyrazo 1 R 4 4-yl) — 1H Pyrazole-3-Carboyl] —4-Methyl-3-oxoxo Perazine

[0903] [Chemical 209]

[0904] 1- (6-Methoxy-1-pyridyl) of Reference Example 61 5- (1-Methyl 1H pyrazole —4-yl) 1H Pyrazole-3-carboxylic acid (0.200 g) and 4 Methyl of Reference Example 21 —3 —The title compound (92. Omg, 35%) was obtained as a solid in the same manner as in Example 5 using oxopiperazine hydrochloride (0.201 g).

 'H-NMR (400MHz, CDC1) δ: 3.01 (3Η, s), 3.45—3.47 (2Η, m), 3.8

 Three

 8 (3H, s), 4.00 (3H, s), 4.03 (IH, m), 4.42 (2H, m), 4.80 (IH, m), 6. 82-6.92 (2H, m), 7.19—7.30 ( 2H, m), 7.59—7.61 (IH, m), 8.20 (1 H, m).

 EI— MSmZz: 395 (M +).

[0905] [Example 122] 1— [1— (6-Methoxy-1-pyridyl) 5-- (1-methyl 1H pyrazol-luoyl 4-yl) 1H pyrazole- 3-carbol] 2-force rubamoylpiperidine [0906] ] [Chemical 210]

[0907] 1- (6-Methoxy-1-pyridyl) of Reference Example 61 5- (1-Methyl 1H pyrazole-4-yl) 1H Pyrazole-3-carboxylic acid (0.250 g) and 2-carbamoylbi of Reference Example 71 The title compound (0.225 g, 64%) was obtained as a solid in the same manner as in Example 5 using peridine (0.118 g).

 'H-NMR (400MHz, CDC1) δ: 1.56— 1.77 (5Η, m), 2.29— 2.40 (1Η,

 Three

 m), 2.78-3.20 (1Η, m), 3.88 (3Η, s), 3.99 (3H, s), 4.69—4.79 (1H, m), 5.36-5.48 (2H, m), 6.38— 7.15 (1H, m), 6.81— 6.86 (2H, m), 7.21-7.23 (1H, m), 7.30 (1H, s), 7.54— 7.61 (1H, m), 8.18— 8.23 (1H, m).

EI-MSm / z: 409 (M ⁺ ).

[0908] [Example 123] 1— [1- (6-Methoxy-3 pyridyl) -5- (2 pyridyl) 1H-virazol-3-carbol] hexahydropyridazine

[0909] [Chemical 211]

参考例 3の 1— (6—メトキシ一 3 ピリジル） 5— (2 ピリジル） 1H ピラゾー ルー 3—力ルボン酸（1.495g)と参考例 20のへキサヒドロピリダジン（0.629g)を用 いて、実施例 1と同様の方法で、標題化合物（1.61g, 87%)をアモルファスとして得 た。

1- (6-Methoxy-3-pyridyl) of Reference Example 3 5- (2 Pyridyl) 1H Pyrazolu 3-Hydroxylic acid (1.495 g) and Hexahydropyridazine (0.629 g) of Reference Example 20 were used. In the same manner as in Example 1, the title compound (1.61 g, 87%) was obtained as amorphous. It was.

 'Η-NMR (400MHz, CDCl) δ: 1.60—1.90 (4H, m), 2.95— 3.10 (2H,

 Three

 m), 3.80-3.90 (1 / 3X2H, m), 3.95 (2 / 3X3H, s), 3.97 (1 / 3X3H, s

), 4.20-4.27 (2 / 3X2H, m), 6.75 (1H, d, J = 8.8Hz), 7.17 (1H, s), 7

.20-7.75 (5H, m), 8.12 (1H, br), 8.5 (1H, br).

 FAB MSm / z: 365 (M + H) +.

[0911] [Example 124] 1— [1— (6-Methoxy-3-pyridazil) 5— (1-Methyl-1H pyridine 3-yl) 1 H Pyrazole 3 carb] 4 Methyl 3oxopiperazine

[0912] [Chem 212]

[0913] Reference Example 55-1 (6-Methoxy-3-pyridazil) -5- (1-Methyl-1H-Pyrroyl 3-yl) -1H Pyrazole-3-carboxylic acid (0.202 g) and Reference Example 21 1 The title compound (0.189 g, 71%) was obtained as an amorphous substance in the same manner as in Example 5 using —methylbiperazine-2-one hydrochloride (0.160 g).

 'H-NMR (400MHz, CDCl) δ: 3.01 (3Η, s), 3.45 (2Η, br), 3.62 (3H, s

 Three

 ), 4.03 (1H, br), 4.20 (3H, s), 4.34—4.45 (2H, m), 4.83 (1H, br), 6.00-6.10 (1H, m), 6.53 (1H, t, J = 2.4Hz), 6.79 (lHXl / 2, br), 6.86 (1H, s), 6.90 (lHXl / 2, br), 7.03— 7.15 (1H, m), 7.50 (lHXl / 2, d, J = 8.8 Hz), 7.65 (lHXl / 2, d, J = 8.8Hz).

 ESI— MSm / z: 396 (M + H) +.

[0914] [Example 125] 1— [1— (6-Methoxy-1-pyridyl) 5— (2 Pyridyl) 1H-virazole 3 carb] 2— (1 aminocyclopropyl) piperidine [0915] [Chemical 213]

[0916] 1) 1— (6-Methoxypyridine 1-yl) 5— (Pyridine 1-yl) 1H-virazole 3 carb] 2— [1 1 (N-tert-butoxycarboluamino) ) Cyclop Mouth Pill] Piperidine

 1- (6-methoxypyridine-3-yl) -5- (pyridine-2-yl) -1H-pyrazole 3 carboxylic acid (184 mg) in Reference Example 3 and 2- [1- (N — Tert-Butoxycarbo-lumino) cyclopropyl] piperidine (149 mg) and 1- [1- (6-methoxypyridine-3-yl) -5- (Pyridine-2-yl) 1H pyrazole 3 carbol] 2-[1 N-tert butoxycarbo-lamino) cyclopropyl] piperidine (308 mg, 96%) was obtained as an amorphous substance.

ESI-MSm / z: 519 (M + H) ⁺ .

[0917] 2) Title compound

 1- [1— (6-Methoxypyridine 1-yl) -5- (Pyridine 1-yl) 1H— Pyrazole 3 carbo] 2 — [1 1 (N— tert-butoxycarbolamino) To a solution of cyclopropyl] piperidine (307 mg) in dichloromethane (20 ml) was added trifluoroacetic acid (7 ml) at room temperature and stirred for 85 minutes. To the residue obtained by distilling off the solution of the reaction solution under reduced pressure, a saturated aqueous solution of sodium bicarbonate and chloroform methanol (10: 1) were vigorously separated. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure to give the title compound (105 mg, 43%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 0.85—1.82 (11Η, m), 2.32—2.35 (1Η

 Three

, m), 2.58-2.64 (1Η, m), 3.10 (1Η, d, J = ll.5), 3.96 (3Η, s), 6.76 (1Η, dd, J = 8.8, 0.7Hz), 7.20—7.23 (2H, m), 7.31 (1H, s), 7.42 (1H , d, J = 7.8Hz), 7.61 (IH, dd, J = 8.8, 2.7Hz), 7.70 (1H, td, J = 7.8,

1.9Hz), 8.10 (1H, d, J = 2.2Hz), 8.48 (IH, d, J = 4.9Hz).

ESI-MSm / z: 419 (M + H) ⁺ .

[0918] [Example 126] 1- [1 (6-Methoxy-3 pyridyl) -5 (thiazole-4 yl)

1H-pyrazole 3 carbonyl] 4 methyl 3oxopiperazine

[0919] [Chemical 214]

[0920] 1- (6-Methoxy-3-pyridyl) -5- (thiazole 4-yl) 1H of pyramid 3 carboxylic acid (0.250 g) in Reference Example 64 and 1-methylbiperazine 2-one hydrochloride of Reference Example 21 (0.249) In the same manner as in Example 5, the title compound (0.239 g, 73%) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 3.02 (3Η, s), 3.46—3.49 (2Η, m), 3.9

 Three

 9 (3H, s), 4.04 (IH, m), 4.43 (2H, m), 4.82 (1H, m), 6.82 (1H, d, J = 8

.8Hz), 7.22-7.30 (2H, m), 7.59— 7.67 (1H, m), 8.16— 8.19 (1H, m

), 8.79 (1H, d, J = 2.0Hz).

 EI— MSmZz: 398 (M +).

[0921] [Example 127] 1- [1 (6-Methoxy-3 pyridyl) -5 (thiazole-4 yl)

1H-pyrazole 3 carbonyl] 4 methylbiperazine

[0922] [Chemical 215]

[0923] Using Reference Example 64 1- (6-Methoxy-3-pyridyl) -5- (thiazole 4-yl) 1H-pyrazole-3-carboxylic acid (0.250 g) and N-methylbiperazine (0.183 ml) In the same manner as in Example 5, the title compound (0.232 g, 73%) was obtained as a solid. 'H-NMR (400MHz, CDC1) δ: 2.38 (3Η, s), 2.53—2.58 (4Η, m), 3.8

 Three

 9 (2H, m), 3.97 (3H, s), 4.14 (2H, m), 6.80 (1H, dd, J = 8.8, 0.5Hz),

7. 14 (1H, s), 7.25 (1H, d, J = 2.0Hz), 7.62 (1H, dd, J = 8.8, 2.9Hz),

8.17-8.18 (1H, m), 8.79 (1H, d, J = 2.0Hz).

EI-MSm / z: 384 (M ⁺ ).

[0924] [Example 128] 1- [1 (6-Methoxy-3 pyridyl) -5 (thiazole-4 yl)

1H-pyrazole 3 carbonyl] 4-methoxypiperidine

[0925] [Chem 216]

参考例 64の 1— (6—メトキシ— 3 ピリジル） -5- (チアゾール—4—ィル）—1H ーピラゾールー 3—力ルボン酸（0.250g)と参考例 23の 4ーメトキシピペリジン塩酸 塩 (0. 188g)とを用いて、実施例 5と同様の方法で、標題化合物（0.295g, 89%) を固体として得た。

Reference Example 64 1- (6-Methoxy-3-pyridyl) -5- (thiazole-4-yl) -1H-pyrazole-3-strong rubonic acid (0.250 g) and 4-methoxypiperidine hydrochloride salt of Reference Example 23 (0 In the same manner as in Example 5, the title compound (0.295 g, 89%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.68— 1.94 (4Η, m), 3.38 (3Η, s), 3.4

 Three

7-3.55 (2H, m), 3.70—3.75 (1H, m), 3.98 (3H, s), 4.09 (1H, m), 4. 27 (1H, m), 6.79— 6.81 (IH, m), 7.11 (1H, s), 7.25— 7.26 (IH, m), 7.63 (1H, dd, J = 8.9, 2.8Hz), 8.17— 8.18 (1H, m), 8.79 (1H, d, J = 2. OHz).

 EI— MSmZz: 399 (M +).

[0927] [Example 129] 1- [1 (6-Methoxy-3-pyridyl) -5 (thiazole-4-yl)

1H-pyrazole 3 carbonyl] 2 strength ruberamoyl biperidine

[0928] [Chemical 217]

[0929] 1- (6-Methoxy-3-pyridyl) -5- (thiazole 4-yl) 1H-pyrazole 3-strong rubonic acid (0.250 g) in Reference Example 64 and piperidine 2-strong rubonic acid amide in Reference Example 71 (0.138 g) was used in the same manner as in Example 5 to obtain the title compound (0.255 g, 75%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.53— 1.83 (5Η, m), 2.30— 2.40 (1Η,

 Three

 m), 2.80-3.21 (IH, m), 3.98 (3H, s), 4.71—4.74 (IH, m), 5.36— 5.49 (2H, m), 6.38— 7.08 (IH, m), 6.79— 6.83 (1H, m), 7.15-7.30 (2H, m), 7.56-7.65 (1H, m), 8.13-8.19 (1H, m), 8.80 (1H, s).

 EI-MSm / z: 412 (M +).

 [0930] [Example 130] 4- [1- (6-Methoxy-3-pyridazinyl) -5 (thiazole-4-yl) 1H-pyrazole-3 carbo] morpholine

[0931] [Chemical 218]

[0932] Using Reference Example 73 1- (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) 1H pyrazole mono 3-carboxylic acid (0.250 g) and morpholine (86 1) In the same manner as in Example 5, the title compound (0.231 g, 74%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 3.73— 3.83 (6Η, m), 4.09—4.12 (2Η,

 Three

 m), 4.15 (3Η, s), 7.14— 7.16 (2H, m), 7.66 (1H, m), 7.76 (1H, d, J =

9.0Hz), 8.73 (1H, d, J = 2.0Hz).

EI-MSm / z: 372 (M ⁺ ).

[0933] [Example 131] 1— (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) 1 H pyrazole 3 carbonyl] 4 Methylpiperazine

[0934] [Chem 219]

参考例 73の 1— (6—メトキシ— 3 ピリダジ -ル）—5— (チアゾール—4—ィル） - 1H ピラゾールー 3—カルボン酸（0.250g)と N—メチルビペラジン（0.110ml)と を用いて、実施例 5と同様の方法で、標題化合物（0.225g, 71%)を固体として得 た。

Using Reference Example 73 1- (6-methoxy-3pyridazil) -5- (thiazole-4-yl) -1H pyrazole-3-carboxylic acid (0.250 g) and N-methylbiperazine (0.110 ml) In the same manner as in Example 5, the title compound (0.225 g, 71%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.35 (3Η, s), 2.46—2.54 (4Η, m), 3.8

 Three

7 (2H, m), 4.06 (2H, m), 4.14 (3H, s), 7.12 (1H, s), 7.15 (1H, d, J = 9.3Hz), 7.66 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J = 9.3Hz), 8.73 (1H, m) EI— MSmZz: 385 (M +).

[0936] [Example 132] 1— (6-Methoxy-3 pyridazil) -5— (thiazole-4-yl) 1H-pyrazole-3-carbol] —4-methoxypiperidine

[0937] [Chemical 220]

[0938] Reference Example 73 1 (6-methoxy-3-pyridazil) -5 (thiazole-4 yl) 1H Pyrazole-3-strong rubonic acid (0.250 g) and Reference Example 23 4-methoxypiperidine hydrochloride (0 In the same manner as in Example 5, the title compound (0.276 g, 83%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.67—1.95 (4Η, m), 3.38 (3Η, s), 3.4

 Three

 8-3.58 (2H, m), 3.68—3.72 (1H, m), 4.07—4. 11 (1H, m), 4.14 (3H, s), 4.22 (1H, m), 7.09 (1H, s), 7.14 (1H, d, J = 9.3Hz), 7.66 (1H, d, J = 2.0Hz), 7.81 (1H, d, J = 9.3Hz), 8.73 (1H, d, J = 2.0Hz).

 EI MSm / z: 400 (M +).

 [0939] [Example 133] 1- (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) 1H-pyrazole-3 carb] -4,4-difluoropiperidine

 [0940] [Chem 221]

[0941] 参考例 73の 1 （6—メトキシー3 ピリダジ -ル）ー5 （チアゾールー 4 ィル） 1H ピラゾールー 3—カルボン酸（0.250g)と参考例 18の 4, 4 ジフルォロピペリ ジン塩酸塩 (0.156g)とを用いて、実施例 5と同様の方法で、標題化合物（0.266g , 79%)を固体として得た。

[0941] Reference Example 73-1 (6-methoxy-3-pyridazil) -5 (thiazole-4 yl) 1H Pyrazole-3-carboxylic acid (0.250 g) and Reference Example 18, 4, 4 difluoropiperidine hydrochloride (0.156 g) ) To give the title compound (0.266 g, 79%) as a solid in the same manner as in Example 5.

 'H-NMR (400MHz, CDC1) δ: 2.08 (4Η, m), 3.93 (2Η, m), 4. 15 (3H,

 Three

 s), 4.15 (2H, m), 7.15— 7.17 (2H, m), 7.66— 7.67 (1H, m), 7.76 (1H

, d, J = 9.3Hz), 8.73 (1H, d, J = 2.0Hz).

EI-MSm / z: 406 (M ⁺ ).

[0942] [Example 134] 1— [1— (6 Methoxy 3 pyridyl) 5 — (1 Methyl 1H pyrazol luo 4-yl)-1H pyrazole-3-carbol] hexahydropyridazine

[0943] [Chemical 222]

[0944] 1- (6-Methoxy-3-pyridyl) of Reference Example 61 5- (1-Methyl 1H pyrazole-4-yl) -1H pyrazole-3-carboxylic acid (0.250 g) and hexaldehyde of Reference Example 20 The title compound (0.202 g, 66%) was obtained as a solid in the same manner as in Example 5 using pyridazine hydrochloride (0.159 g).

 'H-NMR (400MHz, CDC1) δ: 1.68— 1.83 (4Η, m), 3.03— 3.05 (2Η,

 Three

 m), 3.87 (3H, s), 3.87—4.25 (2H, m), 3.99 (3H, s), 6.80— 6.82 (1H, m), 6.88-6.95 (1H, m), 7.21— 7.28 (2H, m), 7.58-7.60 (1H, m), 8.22-8.23 (1H, m).

EI-MSm / z: 367 (M ⁺ ).

[0945] [Example 135] 1— [1 (6-Methoxy-3 pyridazil) -5 (thiazole-4-yl) 1H-pyrazole-3 carbo] hexahydropyridazine [0946] [Chemical 223]

[0947] Reference Example 73 1- (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) -1H pyrazole-3-strong rubonic acid (0.250 g) and Reference Example 20 hexahydro The title compound (0.208 g, 68%) was obtained as a solid in the same manner as in Example 5 using pyridazine hydrochloride (0.157 g).

 'H-NMR (400MHz, CDC1) δ: 1.70—1.86 (4Η, m), 3.03—3.08 (2Η,

 Three

 m), 3.88-4.22 (2H, m), 4. 15 (3H, s), 7.14— 7.28 (2H, m), 7.67 (1H

, m), 7.78-7.93 (1H, m), 8.73 (1H, m).

EI-MSm / z: 371 (M ⁺ ).

 [0948] [Example 136] 4— [1— (6-Methoxy-1-pyridyl) -5- (1-Methyl 1H pyrazo 1-ru 4 yl) 1H pyrazole-3 carbol] 1,4-oxazepane

 [0949] [Chemical 224]

[0950] Reference Example 61 1- (6-Methoxy-1-pyridyl) 5- (1-Methyl 1H pyrazole —4-yl) —1H Pyrazole-3-carboxylic acid (0.250 g) and Reference Example 74 1, 4 — The title compound (0.267 g, 84%) was obtained as a solid in the same manner as in Example 5 using oxazepan hydrochloride (0.138 g).

 'H-NMR (400MHz, CDC1) δ: 2.00— 2.09 (2Η, m), 3.78— 3.92 (6Η,

 Three

m), 3.88 (3H, s), 3.99 (3H, s), 4.06—4.13 (2H, m), 6.81 (1H, d, J = 8 .8Hz), 6.86-6.87 (1H, m), 7.21— 7.22 (1H, m), 7.28— 7.29 (1H, m

), 7.55-7.59 (1H, m), 8.20- 8.23 (1H, m).

EI-MSm / z: 382 (M ⁺ ).

[0951] [Example 137] 4- [1 (6-Methoxy-3 pyridazil) -5 (thiazole-4-yl) 1H-pyrazole-3 carbol] 1,4-oxazezepan

[0952] [Chemical 225]

[0953] Reference Example 73 1- (6-Methoxy-3 pyridazil) -5- (thiazole-4-yl) -1H pyrazole-3-carboxylic acid (0.250 g) and Reference Example 74 1, 4— The title compound (0.264 g, 82%) was obtained as a solid using oxazepan hydrochloride (0.136 g).

 'H-NMR (400MHz, CDCl) δ: 2.01— 2.11 (2Η, m), 3.80— 3.90 (6Η,

 Three

 m), 4.04-4.09 (2H, m), 4.14 (3H, s), 7.13— 7.16 (2H, m), 7.66— 7

.67 (1H, m), 7.74-7.79 (1H, m), 8.72-8.74 (1H, m).

 EI— MSmZz: 386 (M +).

[0954] [Example 138] 1- [1 (6-Methoxy-3-pyridyl) -5 (thiazole-4 yl)

1H-pyrazole 3 carbo] hexahydropyridazine

[0955] [Chem 226]

参考例 64の 1— (6—メトキシ— 3 ピリジル）—5— (チアゾール—4—ィル）—1H ーピラゾールー 3—力ルボン酸（0.250g)と参考例 20のへキサヒドロピリダジン塩酸 塩 (0. 158g)とを用いて、実施例 5と同様の方法で、標題化合物（0.202g, 66%) を固体として得た。

1- (6-Methoxy-3-pyridyl) -5- (thiazole-4-yl) -1H-pyrazole-3-strong rubonic acid (0.250 g) in Reference Example 64 and hexahydropyridazine hydrochloride in Reference Example 20 The title compound (0.202 g, 66%) was obtained as a solid in the same manner as in Example 5 using the salt (0.158 g).

 'H-NMR (400MHz, CDC1) δ: 1.70—1.83 (4Η, m), 3.04—3.05 (2Η,

 Three

 m), 3.93-4.24 (2H, m), 3.97 (3H, s), 6.80 (1H, d, J = 8.8Hz), 7.16 -7.29 (2H, m), 7.61-7.64 (1H, m), 8.18 — 8. 19 (1H, m), 8.79 (1H, m).

ESI-MSm / z: 371 (M + H) ⁺ .

[0957] [Example 139] 4- [1 (6-Methoxy-3-pyridyl) -5 (thiazole-4 yl)

1H pyrazole-3 carbonyl] -1,4-oxazezepan

[0958] [Chemical 227]

[0959] 1- (6-Methoxy-3-pyridyl) -5- (thiazole 4-yl) 1H-pyrazole-3-strong rubonic acid (0.250 g) of Reference Example 64 and 1,4-oxazepane hydrochloride of Reference Example 74 ( In the same manner as in Example 5, the title compound (0.272 g, 85%) was obtained as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.02— 2.10 (2Η, m), 3.79— 3.89 (6Η,

 Three

 m), 3.97 (3H, s), 4.06—4.12 (2H, m), 6.79 (1H, d, J = 8.8Hz), 7.16

-7. 17 (1H, m), 7.27— 7.28 (1H, m), 7.58— 7.62 (1H, m), 8.15— 8.

18 (1H, m), 8.78-8.79 (1H, m).

 ESI— MSm / z: 386 (M + H) +.

[0960] [Example 140] 1— [5 -— (5-Strength Lumamoylmethoxy-2-pyridyl) —1— (6-Methoxy

—3 Pyridyl) 1H Pyrazole 3-Carbon) 4-methylbiperazine

[0961] [Chemical 228]

[0962] 1) 1— [5— (5 Benzyloxy-2-pyridyl) 1- (6-Methoxy-1-pyridyl)

 1H Pyrazole-3 Carbonyl] -4-methylbiperazine

 Using Reference Example 76, 5- (5 benzyloxy-2-pyridyl) -1- (6-methoxy-3-pyridyl) 1H pyrazole-3-carboxylic acid (1. Og) and N-methylbiperazine (0.280 g) In the same manner as in Example 5, 1- [5— (5 benzyloxy-2 pyridyl) -1-1- (6-methoxy-1-pyridyl) 1H pyrazole-1-3-carboro] —4-methylbiperazine (0.995g, 82 %) Was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.34 (3Η, s), 2.42—2.52 (4Η, m), 3.8

 Three

0-3.90 (2H, m), 3.95 (3H, s), 4.07—4.13 (2H, m), 5.10 (2H, s), 6.75 (1H, d, J = 8.8Hz), 7.03 (1H, s), 7.23—7.41 (7H, m), 7.58 (1H, dd, J = 8.8, 2.7Hz), 8.11 (1H, d, J = 2.7Hz), 8.27 (1H, d, J = 2.7Hz). EI-MSm / z: 484 (M ⁺ ).

[0963] 2) 1— [5— (5 Hydroxy-2-pyridyl) 1- (6-Methoxy-1-pyridyl) 1H Pyrazole 3-carbonyl] 4 Methylbiperazine

 In a methanol (50 ml) solution of 1 [5- (5 benzyloxy-2 pyridyl) -1 (6-methoxy-3-pyridyl) 1H-pyrazole-3-carbol] -4-methylbiperazine (0.990 g) % Palladium on carbon (50% wet, 1. Og) was added, and the mixture was stirred at room temperature for 2 hours in the presence of hydrogen. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and 1 [5- (5 hydroxy-2-pyridyl) 1- (6-methoxy-1-pyridyl) 1H pyrazole-1-carbonyl] 4-methylbiperazine (895 mg, (Quantitative) was obtained as a solid.

 'H-NMR (400MHz, CDCl) δ: 2.55 (3Η, s), 2.75—2.90 (4Η, m), 3.9

 Three

3 (3H, s), 3.93-4.05 (2H, m), 4.25—4.40 (2H, m), 6.72 (1H, d, J = 8.8Hz), 6.98 (1H, s), 7.13— 7.18 (2H , m), 7.51 (1H, dd, J = 6.1, 2.7 Hz), 8.07 (1H, d, J = 2.7Hz), 8.11 (1H, d, J = 2.7Hz).

EI-MSm / z: 394 (M ⁺ ).

[0964] 3) Title compound

 To a solution of the above hydroxy compound in N, N dimethylformamide (10 ml), carbonated lithium (410 mg) and bromoacetamide (250 mg) were added at room temperature and stirred for 20 hours. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (dichloromethane / methanol) to obtain the title compound (150 mg. 23%) as a solid.

 'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 2.45— 2.60 (4Η, m), 3.8

 Three

 0-3.95 (2H, m), 3.95 (3H, s), 4.10—4.20 (2H, m), 5.74 (1H, br s), 6.48 (1H, br s), 6.76 (1H, dd, J = 8.8, 0.7Hz), 7.07 (1H, s), 7.23 (1 H, dd, J = 8.8, 3.2Hz), 7.39 (1H, dd, J = 9.3, 0.5Hz), 7.59 (1H, dd, J = 8.8, 2.7Hz), 8.09 (1H, dd, J = 2.7, 0.7Hz), 8.25 (1H, d, J = 2.4Hz)

EI-MSm / z: 451 (M +).

[0965] [Example 141] 1— [1— (6-Methoxy-3 pyridazil) -5- (1-methyl-1H pyrazole-4 yl) 1H-pyrazole-3 carb] -4, 4-difluoropiperidine

[0966] [Chemical 229]

参考例 77の 1— (6—メトキシ一 3 ピリダジ -ル） 5— (1—メチル 1H ピラゾ 一ルー 4—ィル）—1H ピラゾールー 3—カルボン酸（0.250g)と参考例 18の 4, 4 —ジフルォロピペリジン塩酸塩 (0.157g)とを用いて、実施例 5と同様の方法で、標 題化合物（0.227g, 68%)を固体として得た。 Ή-NMR (400MHz, CDC1 ) δ : 2. 04— 2. 10 (4H, m) , 3. 92 (3H, s) , 3. 9

Reference Example 77 1- (6-Methoxy-1-pyridazil) 5- (1-Methyl 1H pyrazol 4-lu)-1H Pyrazole-3-carboxylic acid (0.250 g) and Reference Example 4, 4, 4 —The title compound (0.227 g, 68%) was obtained as a solid in the same manner as in Example 5 using difluoropiperidine hydrochloride (0.157 g). Ή-NMR (400MHz, CDC1) δ: 2. 04— 2. 10 (4H, m), 3. 92 (3H, s), 3.9

 Three

 2 (2H, m), 4.11 -4. 14 (2H, m), 4.20 (3H, s), 6. 88 (1H, s), 7. 15 (1H, d, J = 9. 3Hz), 7.57 (1H, s), 7.68—7.70 (1H, m), 7.76 (1H, s).

EI-MSm / z: 403 (M ⁺ ).

[0968] [Test Example 1] Inhibition of platelet aggregation

 Human blood was collected using 1Z10 volume of 3.13% sodium quenate as a blood coagulation inhibitor, and centrifuged at 180 g for 10 minutes to separate platelet-rich plasma (PRP). After separating the upper PRP, the lower layer was centrifuged at 1600 g for 10 minutes, and the upper platelet poor plasma (PPP) was collected. The solution of Example Compound 1 μ1 was added to PRP 200 μ1 and allowed to stand at 37 ° C. for 2 minutes, and then collagen 2 μ1 was added to induce platelet aggregation. Platelet aggregation rate was measured using PAM-12C (SSR Engineering). The light transmittance of the cocoon was taken as the 100% aggregation value, and the aggregation rate at each concentration of the example compound was determined.

 50 values were calculated. The results are shown in Table 1.

 [0969] [Test Example 2] Cyclooxygenase-1 (COX—1) and Cyclooxygenase 2 (COX

 2) Verification of inhibitory action

 For the measurement of the COX-1 and COX-2 inhibitory activities of the example compounds, a COX inhibitor screening assay kit (catalog numbers 560101 and 560121) from Cayman Chemical Company was used.

 Reaction buffer, heme, arachidonic acid, SnCl, EIA before measurement

 2 Buffer, wash buffer, prostaglandin (PG) screening EIA standard solution, PG screening acetylcholinesterase (AchE), tracer (chromogenic enzyme HRP conjugate), PG screening EIA antiserum were prepared.

 (l) Production of PGF α by COX-1

 2

 The reaction solution containing Example Compound (50 μΜ) and COX-1 or the reaction solution containing Example Compound (300 M) and COX-2 was allowed to stand at 37 ° C for 10 minutes, respectively, and then arachidonic acid Hold 10 1 and let stand at 37 ° C for 2 minutes. After the reaction, 1N-hydrochloric acid 50 1 was added to stop the reaction, and then SnCl solution 100 1 was added and allowed to stand at room temperature for 5 minutes.

 2

 [0970] (2) Quantification of PGF α by ELISA

 2

Antiserum (in each well of a 96-well plate coated with mouse anti-rabbit IgG) Usagi anti-PGF α antibody) 50 / zl was added, and the above PGF α production reaction solution was increased 2000 times.

twenty two

 The diluted solution 50 1 and AchE tracer 50 1 were sequentially added and allowed to stand at room temperature for 18 hours. Each well was washed 5 times with wash buffer to remove excess AchE tracer and then supplemented with 200 / zL Ellman reagent. After standing in a dark room for 60 minutes, measure the absorbance at 405 nm.

 [0971] (3) Calculation of inhibitory activity of Example compounds

 PG screening A standard curve was prepared using an EIA standard solution, and the amount of PGFa produced was determined using the absorbance power described above. Example compound COX-1 inhibition rate in 50 μΜ and examples

2

 The inhibition rate of COX-2 in the compound 300 M was calculated. The results are shown in Table 1.

 In calculating the inhibition rate, the production amount of PGFα obtained using the reaction solution not containing the Example compound was defined as 100%.

 2

[0972] [Table 1]

Collagen-induced platelet aggregation at 300 in 50 M

 Examples Inhibitory action COX-1 inhibitory action COX-2 inhibitory action

IC ₅₀ (M) (% inhibition) (% inhibition)

1 0. 2 1-1 3.3 NT

 2 0. 1 3 1 1.2 NT

 3 0. 2 2-2 1. 2 NT

 4 0. 2 1-1 3.3 NT

 5 0. 2 1-3 5. 9 NT

 1 0 0. 1 9 54. 1 NT

 1 2 0. 3 2 2 5. 9 NT

 1 4 0. 1 2 3 9. 3 NT

 1 6 0. 1 2-5.2 NT

 1 8 0. 2 0 One 3.0 NT

 2 0 0. 1 2-1 7. 0 NT

 2 7 0. 0 9 1-1 0. 2 NT

 3 1 0. 1 8-1 0. 5 NT

 3 2 0. 2 1-8.4 NT

 3 3 0. 0 9 7-9.5 NT

 3 4 0. 0 6 3-1 8. 4 NT

 3 8 0. 3 7 1.2 NT

 4 1 0. 1 7-2 1. 3 NT

 7 3 0. 1 5 5. 9 1 5.5

 1 0 5 0. 44-9. 6 NT

 1 0 7 0. 4 3 1 3. 9 NT

 1 1 5 0. 1 1 -21. 2 23. 4

 1 1 8 0. 0 7 9-1 2. 7 NT

 1 1 9 0. 1 6 1 3. 0 NT

 121 0. 7 1 —0. 7 NT

 1 24 0. 44 8. 3 NT

 1 2 6 0. 3 6-6.4 NT

 1 2 7 0. 2 3-2 1. 2 NT

 1 2 8 0. 1 0 NT NT

 1 2 9 0. 2 6 NT NT

 1 3 1 0. 3 2 NT NT

 1 3 2 0. 1 9 NT NT

 1 3 3 0. 0 8 NT NT

 1 3 4 0. 0 4 NT NT

 1 3 6 0. 3 6 NT NT

 1 3 7 0. 0 8 NT NT

 1 3 8 0. 04 1 NT NT

 1 3 9 0. 0 4 1 NT NT

 1 4 1 0. 1 9 2 4. 4 NT

 NT: Not Tested

As is clear from Table 1, the compound (I) of the present invention, a salt, a solvate thereof, or a solvate of the salt has a strong platelet aggregation inhibitory action, and COX-1 and COX— The force showed no inhibitory effect.

Claims

Claim [1] General formula (I)  [Chemical 1]

[Where Αι ^ is the general formula (II)  [Chemical 2]

(Wherein Y represents CH or a nitrogen atom, R ¹ represents a lower alkyl group or a lower alkoxy group);  Ar is a lower alkyl group which may be substituted, a lower alkynyl group, which may be substituted 2  A certain rubermoyl group, a cyano group, an amino group which may be substituted, a lower alkoxy group which may be substituted and a lower alkanol group which may be substituted with 1 to 3 groups selected 5 or Represents a 6-membered aromatic heterocyclic group;  X is the general formula (III) [Chemical 3]

(The cyclic structure in the formula may have a nitrogen atom or an oxygen atom other than the nitrogen atom described in the above formula as a constituent atom, may be substituted lower alkyl group, may be substituted A certain rubermoyl group, an amino group that may be substituted, a hydroxyl group, a lower alkoxy group, an oxo group, a lower alkanol group, a lower alkyl sulfol group, and a halogen nuclear atom. And a 4- to 7-membered alicyclic heterocyclic group which may be substituted. ) Is represented. ]  Or a salt or a solvate thereof. [2] Ar 1S Lower alkyl group which may be substituted, lower alkynyl group, which may be substituted  2  A certain ruberamoyl group, a cyano group, an amino group that may be substituted, a lower alkoxy group that may be substituted, and a lower alkanol group may be substituted with 1 to 2 groups selected! / 2. The compound according to claim 1, a salt thereof, or a solvate thereof, which is a 5-membered nitrogen-containing aromatic heterocyclic group.  [3] The compound, its salt or solvate thereof according to claim 2, wherein the 5-membered nitrogen-containing aromatic heterocyclic group is a pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group or triazolyl group. object.  [4] Five-membered nitrogen-containing aromatic heterocyclic group is 1H-pyrrole 1-yl group, 1H-pyrrole 2-yl group, 1H-pyrrole 3-yl group, 1H-imidazole 2- Group, 1H-imidazole-4-yl group, 1H pyrazole-3-yl group, 1H pyrazole-4-yl group, thiazole-2-yl group, thiazole-4-yl group, thiazole-5-yl group, oxazol-free 2- The compound according to claim 2, a salt thereof, or a solvate thereof, wherein the compound is an alkyl group, an oxazole-4-yl group, or a 1H—1, 2,4 triazo-lru 3-yl group. [5] Ar may be substituted lower alkyl group, lower alkyl group, may be substituted  2  A rubamoyl group, a cyano group, an amino group which may be substituted, a lower alkoxy group which may be substituted and a lower alkanoyl group which may be substituted with 1 to 2 groups which may be selected. 2. The compound according to claim 1, which is a nitrogen-containing aromatic heterocyclic group, a salt thereof, or a solvate thereof.  [6] The compound, salt or solvate thereof according to claim 5, wherein the 6-membered nitrogen-containing aromatic heterocyclic group is a pyridyl group, a pyrimidyl group or a pyradyl group. [7] 6-membered nitrogen-containing aromatic heterocyclic group is 2 pyridyl group, 4 pyrimidyl group or 2-villa 6. The compound according to claim 5, a salt thereof or a solvate thereof, which is a dinyl group. [8] The general formula (III) may be substituted with a lower alkyl group which may have a nitrogen atom as a constituent atom in addition to the nitrogen atom described in the above formula (III), or may be substituted. 1 to 4 groups or atoms selected from a certain rubermoyl group, an optionally substituted amino group, a hydroxyl group, a lower alkoxy group, an oxo group, a lower alkanol group, a lower alkylsulfol group and a halogen atom The compound, a salt thereof or a solvate thereof according to claim 1, wherein the compound is a 5-membered alicyclic heterocyclic group, which is substituted. [9] The compound according to claim 8, a salt thereof or a solvate thereof, wherein the 5-membered alicyclic heterocyclic group is a pyrrolidinyl group or a virazolidinyl group. [10] The group represented by the general formula (III) may have a nitrogen atom or oxygen atom as a constituent atom in addition to the nitrogen atom described in the general formula (III), or may be substituted. Also selected are alkyl groups, optionally substituted rubermoyl groups, optionally substituted amino groups, hydroxyl groups, lower alkoxy groups, oxo groups, lower alkanol groups, lower alkyl sulfol groups and halogen atomic energy 1 The compound according to any one of claims 1 to 7, a salt thereof, or a solvate thereof, which is a 6-membered alicyclic heterocyclic group which may be substituted with ~ 4 groups or atoms.  [11] The compound according to claim 10, wherein the 6-membered alicyclic heterocyclic group is a piperidino group, piperazino group, hexahydropyridazine 1-yl group or morpholino group. [12] X force 2 methylpyrrolidino group, 2,5 dimethylpyrrolidino group, 2 fluoromethylpyrrolidino group, 2-trifluoromethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 2-methoxymethyl- 5 Methylpyrrolidino group, 2—Strong ruberamoylpyrrolidino group, 3 Fluoropyrrolidino group, 3, 3 Difluoropyrrolidino group, 2 Methylvirazolidine 1-yl group, 2 Formylpyrazolidine 1-yl group, 2 —Methylsulfo-pyrazolidine 1-yl group, piperidino group, 3-methoxypiperidino group, 3-fluoropiperidino group, 4-methylbiperidino group, 4-methoxypiperidino group, 4-fluoropiperidin group Group, 4,4-difluoropiperidino group, 2 aminocyclopropylpiperidino group, 3 oxo 4-methylbiperazino group, 3- oxo-4-ethylbiperazino group, 4-methylbipe Razino group, hexahydropyridazine 1-yl group, morpholino group, 3 methylmorpholine 4-yl group and 1,4-oxazezepa The compound according to any one of claims 1 to 7, its salt, or a solvate thereof. [13] X is a morpholino group, 4-methoxy piperidinocarbonyl group, a 4 Full O Ropi piperidino group or 4, 4 difluoromethyl O Ropi piperidino group, R ¹ is a lower alkyl group, according to claim 1 Compound.  [14] 4— [1— (6-Methoxy-1-pyridyl) -5- (1-methyl-1H pyrazole-4-yl) 1H-pyrazole-3 carbo] morpholine. [15] A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. [16] A platelet aggregation inhibitor comprising the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. [17] A prophylactic and Z or therapeutic agent for ischemic disease comprising the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. [18] A medicament comprising the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof as an active ingredient. [19] A platelet aggregation inhibitor comprising the compound according to any one of claims 1 to 14, a salt thereof, or a solvate thereof as an active ingredient. [20] A prophylactic and Z or therapeutic agent for ischemic disease comprising the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof as an active ingredient. [21] A method for the prevention and Z or treatment of ischemic disease, comprising administering an effective amount of the compound, salt or solvate thereof according to any one of claims 1 to 14. [22] Use of the compound according to any one of claims 1 to 14, a salt thereof or a solvate thereof for the production of a medicament.